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Title Synthesis of Functionalized Organoboron Compounds through Copper(I) Catalysis
Author(s) 久保田, 浩司
Citation 北海道大学. 博士(工学) 甲第12334号
Issue Date 2016-03-24
DOI 10.14943/doctoral.k12334
Doc URL http://hdl.handle.net/2115/64815
Type theses (doctoral)
File Information Koji_Kubota.pdf
Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP
1
Synthesis of Functionalized Organoboron
Compounds through Copper(I) Catalysis
Koji Kubota
2016
2
Table of Contents
General Introduction
Chapter 1 Copper(I)‐Catalyzed Direct Boryl Substitution of
Unactivated Alkyl Halides
Chapter 2 Copper(I)‐Catalyzed Intramolecular Borylative
exo‐Cyclization of Alkenyl Halides Containing
Unactivated Double‐Bond
Chapter 3 Copper(I)‐Catalyzed Regio‐ and Enantioselective
Monoborylation of Alkenylsilanes
Chapter 4 Copper(I)‐Catalyzed Enantioselective Nucleophilic
Borylation of Aldehydes
Chapter 5 Computational Insight into the Enantioselective
Borylation of Aldehydes Catalyzed by Chiral
Bisphosphine Copper(I) Complexes
Chapter 6 Copper(I)‐Catalyzed Enantioselective Borylative
Dearomatization of Indoles
Chapter 7 Copper(I)‐Catalyzed Regio‐ and Enantioselective
Borylation of 1,2‐Dihydropyridines
Summary of this thesis
List of Publications
Acknowledgments
3
General Introduction
Structurally, organoborons are trivalent boron‐containing organic
molecules with six valence electrons and a consequent deficiency of two
electrons at the boron center, which possess a vacant p orbital and show a
Lewis acidic character. Therefore, triakylboranes or trihaloboranes are
generally highly reactive and air‐sensitive reagents. Boronate esters, the main
precursors for boronic acid derivatives, are most often used in organic
chemistry as well as other broad scientific fields, which possess one organic
group and two oxygenated substituents to lower the Lewis acidity of a boron
atom through the hyperconjugation between a lone pair of oxygen and a
vacant p orbital of boron center (Figure 1). Their unique properties as mild
organic Lewis acids and their mitigated reactivity, coupled with their
stability and ease of handling, makes boronic acid derivatives a very
attractive class of nucleophilic organometallic reagents. Furthermore,
considering their low toxicity, boronic acid derivatives can be regarded as the
environmentally friendly “green” organic molecules.
Figure 1. Oxygenated Organoboron Compounds
Boronate esters are readily prepared by simple dehydration of boronic
acids with alcohols. By losing the hydrogen bond in the hydroxyl groups,
boronate esters are less polar and easier to handle and purification than
boronic acids. They also serve as protecting groups to control and ture their
reactivity of boron‐carbon bonds. Thus, there are many types of boronic
esters including chiral auxiliaries have been synthesized for organic synthetic
R1 B
R2
R3
R B
OH
OH
R1 B
OR2
OR3
borane boronic acid boronic ester
4
applications (Figure 2).
Figure 2. Common Boronic Esters in Organic Synthesis
As for the reactivity of organoboron compounds, they have quite milder
nucleophilicity compared to other organometallics such as organolithium,
organomagnesium, and organozinc reagents because the ionic character of a
carbon‐boron bond is relatively lower than those of the reagents. Thus,
organoboronate esters have significant advantages because they can be easily
purified prior to utilization and have reasonable shelf stability under normal
atmospheric conditions. When an appropriate activation procedure is
employed, organoboron compounds are also sufficiently reactive for the use
in synthetic chemistry, especially as reagents for transition‐metal‐catalyzed
cross‐coupling reactions with various electrophiles (Figure 1).2 The
attribution of the 2010 Chemistry Nobel Prize for palladium‐catalyzed
cross‐coupling reactions, shared by Professor Akira Suzuki, cements the
importance of organoborons in CC bond forming processes (Figure 3).
R1 B(OH)2 +
R2 OH2
HO
HO
or
R1 B(OR2)2
or
R1 BO
O
+ H2O
R BOiPr
OiPr
R BO
OR B
O
OR B
O
OR B
O
O
R BO
OR1 B
O
O CO2R2
CO2R2
R1 BO
O R2
R2
R BO
O
5
Figure 3. Fundamental Property of Organoboron Reagents
Moreover, enantioenriched chiral alkylboronate esters have been
recognized as important chiral building blocks in organic synthesis because
they undergo stereospecific transformations of the stereogenic C−B bonds to
form C−O, C−N, or C−C bonds (Figure 4).3
Figure 4. Stereospecific Transformations of Enantioenriched Alkylboronate
Esters
In addition to their great synthetic utility, organoboron compounds have
been used in other scientific fields, such as medicinal chemistry.1 For
examples, chiral boronic acid Bortezomib has been widely used as malignant
lymphoma therapeutics. Furthermore, Tavaborole has been known to show
an antimycotic property (Figure 5).
C B
Low Ionic Characterof CB Bond
Vacant p Orbital
Nu
CB
Nu
High Stability
High Reactivity
B
R1 R2
H
C
R1 R2
H
O
R1 R2
H
N
R1 R2
H
CC Bond Formation
CO Bond Formation
CN Bond Formation
6
Figure 5. Boron‐Containing Pharmaceutical Drugs
Recently, a triarylboryl group has been utilized in material chemistry
because the optical properties can be controlled by π‐accepter character of a
boryl group. For examples, the platinum complex bearing the
boron‐contaning ligand has been reported to be a potential organic
electroluminescence element (Figure 6).4
Figure 6. Selected Example for Boron‐Containing Organic EL
Organoboronates are most often prepared through the transmetalation
between organomagnesium or organolithium reagents and electrophilic
boron precursors (Sheme 1a). However, these methods suffer from poor
functional group tolerance. Hydroboration of alkenes is one of the most
efficient and straightforward protocols to access alkylboronic esters. This
method has also significant limitation, such as regioselectivity issue in the
case of hydroboration of internal alkenes (Scheme 1b).
N
NNH
OHN
O
BOH
OH
BortezomibMalignant lymphoma therapeutics
OB
F
OH
TavaboroleAntimycotic therapeutics
N NN
PtO O
B
7
Scheme 1. Conventional Synthetic Routes to Organoboronate Esters
Conventional synthetic approaches toward optically active
organoboronates are shown in Scheme 2. Brown’s asymmetric hydroboration
using (+)‐diisopinocamphenylborane (Ipc2BH) is one of the most practical
and scalable protocols to access chiral boron compounds with high
enantiometric purity (Scheme 2a). Homologation methodology using organo
lithium compound and ()‐sparteine with boron electrophile also produces
the chiral boronate with high enantiometric excess (Scheme 2b). However,
these reactions require stoichiometric amount of chiral auxiliary. Considering
this drawback, catalytic asymmetric borylation reaction is a highly desirable
method for the construction of a stereogenic CB bond. In 1989, Prof.
Hayashi and Prof. Ito reported the first transition‐metal‐catalyzed
enantioselective hydroboration of styrenes to afford the corresponding chiral
boronate with an excellent enantioselectivity (Scheme 2c).5 Despite the great
utility of this catalytic approach, the development of the method has been
less explored for other prochiral alkenes.
B
H B
R2R1
R1 H
R2
+R1 B
R2
R XMg
R MgX
X B
R B
b) Hydroboration
a) Transmetalation
Low Functional Group ToleranceStoichiomeric Reaction
Regioselectivity ProblemNarrow Substrate Scope
8
Scheme 2. Selected Studies on the Synthesis of Chiral Organoboron
Compounds
Transition‐metal‐catalyzed borylation reactions have emerged as an
alternative and powerful tool for the production of various organoboronate
esters, which have been the subject of extensive research during the past
several years.1b Significant efforts have been focused on the investigation of
catalytic borylation of C(sp2)−X and C(sp2)−H bonds of alkenes or arenes for
the synthesis of alkenyl‐ or arylboronates (Scheme 3).6 However,
transition‐metal‐catalyzed highly useful and practical borylations for
alkylboron synthesis are not well explored.
BH
2
+
H B(ipc)2 H OH
OPh
N(i-Pr)2
O s-BuLi
()-sparteine
Et BO
O
B(pin)Ph
Et
b) Homologation
a) Brown Asymmetric Hydroboration
+O
HBO
[Rh(cod)2]BF4 (1 mol %)(R)-BINAP (1 mol %)
78 C, 6 h
B(cat)
c) Catalytic Enantioselective Borylation
99% ee
90%, 96% ee
91%, 96% ee
9
Scheme 3. Examples of Transition‐Metal‐Catalyzed Borylation for the
Construction of C(sp2)−B Bond: Miyaura‐Ishiyama‐Hartwig Borylation
In 2000, the borylation reactions of α,β‐carbonyl compounds using
copper(I)/diboron catalytic system, which provided the corresponding
1,4‐boryl addition products, were developed by Hosomi and Ito, and
Miyaura and Ishiyama groups independently (Scheme 4).7,8 These reactions
are the first examples of activation of a B–B bond with a copper(I) salt to
generate nucleophilic borylcopper(I) species.
Scheme 4. Copper(I)‐Catalyzed Borylation of Conjugated Enone
These reactions have various advantages over classical procedures for the
synthesis of alkylboronate esters (Scheme 5). In the presence of a copper(I)
salt and diboron, σ‐bond metathesis occurs to generate nucleophilic
borylcopper(I) intermediates. Unlike conventional stoichiometric “boron
electrophilic reaction” methods, this reaction does not require stoichiometric
amounts of highly reactive carbon nucleophiles such as Grignard reagents or
organolithium compounds. Moreover, this reaction can be applied to
C X + B Bcat. PdCl2 (dppf)
KOAc / DMSOC B
R R
Miyaura Borylation
sp2
C H + B Bcat. [Ir(cod)(OMe)]2
C B
R R
C-H Borylation
sp2
N Ndtbpy
dtbpy
Ph Ph
OB B
O
O O
O+
Cu cat.
Ph Ph
OBOO
with CuX/PBu3 cat.: Hosomi and Itowith CuCl/KOAc cat.: Miyaura and Ishiyama
1,4-Addition
10
catalytic enantioselective borylation reaction by introducing appropriate
chiral ligands.
Scheme 5. Generation and Reactivity of Borylcopper(I) Intermediate
Since then, Ito, Sawamura, and co‐workers reported several asymmetric or
non‐asymmetric borylations using copper(I)/diboron catalytic systems.9,10 In
the presence of a copper(I) catalyst and diboron, allylic carbonates were
converted into the corresponding allyboronate esters with almost complete
chirality‐transfer and γ‐selectivity (Scheme 6).9a The observed stereochemical
outcome can be explained by the SN2’‐attack of borylcopper(I) spicies to an
allylic carbonates in a comformation that avoids an allylic 1,3‐strain.
CuO
BB
L
R
Cu BCu OR
B B
Borylcopper(I) Spicies
R M X B + R B
Boron Electrophile
Stoichiometric Reaction
Harsh Reaction Conditions
Narrow Substrate Scope
Cu BR X R B
Boron Nucleophile
Catalytic Reaction
Mild Reaction Conditions
Good Functional Group Tolerance
-Bond Metathesis
11
Scheme 6. Stereospecific Borylation of Allylic Carbonates
Enantioselective borylation reactions were also performed with an chiral
bisphosphine ligand QuinoxP*.9b The reaction of prochiral (Z)‐allylic
carbonate with diboron in the presence of copper(I)/(R,R)‐QuinoxP* catalyst
afforded the corresponding optically active allylboronates with excellent
enantioselectivity (Scheme 7).
Scheme 7. Copper(I)‐Catalyzed Enantioselective Boryl Substitution of Allylic
Carbonates
In the reaction of 3‐silylated allylic carbonates with
copper(I)/(R,R)‐QuinoxP* catalyst, the optically active boron‐silicon
bifunctional cyclopropane derivatives were obtained exclusively instead of
allylboron compounds (Scheme 8).9c
12
Scheme 8. Asymmetric Borylative Cyclization of Silyl Substituted Alkenes
Regio‐ and enantioselective protoborylation of conjugated 1,3‐diene using
chiral copper(I) catalysis has also been devolped.9e The reaction of
cyclohexadiene in the presence of Cu(O‐t‐Bu)/(R,R)‐Me‐Duphos and MeOH
as a proton source proceeded to give the chiral homoallylic boronate with
excellent regio‐ and enantioselectivity (Scheme 9).
Scheme 9. Regio‐ and Enantioselective Borylation of Conjugated 1,3‐Diene
The author also focuses on the reactivity of nucleophilic borylcopper(I)
complex and pursues the development of novel catalytic borylation reactions
based on above results. This thesis describes several new types of reactions
13
for alkylboron synthesis: direact boryl substitution of unactivated alkyl
halides (Chapter 1), borylative exo‐cyclization of alkenyl halides containing
unactivated C−C double bond (Chapter 2), regio‐ and enantioselective
protoborylation of alkenylsilanes by using copper(I)/BenzP* complex
catalysis (Chapter 3), enantioselective nucleophilic borylation of aldehydes
by using copper(I)/DTBM‐SEGPHOS complex catalysis (Chapter 4) and
enantioselective synthesis of chiral borylpiperidines through regio‐ and
enantioselective protoborylation of 1,2‐dihydropyridines by using
copper(I)/QuinoxP* or SEGPHOS complex catalysis (Chapter 5).
Chapter 1 describes the copper(I)/Xantphos‐catalyzed boryl substitution of
unactivated alkyl halides (Scheme 9).11,12 This reaction is the first practical
procedure for direct boryl substitution of unactivated alkyl halides. This
reaction offers a direct umpolung pathway for the conventional carbon
nucleophile methods, and has high functional group compatibility and
interesting stereochemical‐controlling properties. This novel protocol will be
a powerful synthetic method for a broad range of alkylboronates, including
those that could not be synthesized by previous methods.
Scheme 9. Copper(I)‐Catalyzed Boryl Substitution of Unactivated Alkyl
Halides
Chapter 2 describes the copper(I)/Xantphos‐catalyzed borylative
exo‐cyalization of alkenyl halides (Scheme 10).13 This reaction based on the
+O
BO
BO
O
(1.2 equiv)
3 mol % CuCl3 mol % Xantphos
K(O-t-Bu) (1.0 equiv)THF, rt, 4 h
Br B(pin)
94%
BCuO
PPh2
PPh2
BrHigh Functional Group Tolerance
Regiospecific Borylation
Formal Nucleophilic Boryl Substitution
14
unprecedented regioselective borylation reaction of unactivated alkenes
using copper(I) catalyst. The reaction includes the regioselective addition of a
borylcopper(I) intermediate to unactivated terminal alkenes, followed by the
intramolecular substitution of the resulting alkylcopper(I) moiety for the
halide leaving groups. To understand the reaction mechanism and the
reactivity of borylcopper(I) complexes toward alkenes, density functional
thory (DFT) calculations have also been conducted. This reaction provides a
new method for the synthesis of alkylboronates containing strained
cycloalkyl structures from simple starting materials.
Scheme 10. Copper(I)‐Catalyzed Borylative exo‐Cyclization of Alkenyl
Halides
Chapter 3 describes the highly regio‐ and enantioselective protoborylation
of alkenylsilanes catalyzed by an electron‐donating chiral copper(I)/BenzP*
complex (Scheme 11).14,15 This is the first example of asymmetric β‐borylation
of (Z)‐alkenylsilane substrates to provide enantiomerically enriched vicinal
borosilanes, which can be derivatized through stepwise, stereospecific
transformations of the boron and silicon functionalities. The reaction of
various alkenylsilanes bearing functional groups, such as silyl ether, cyano
and ester proceeded in high yields with excellent enantioselectivities. The
synthetic utility of this protocol was demonstrated by the stepwise and
stereoselective transformation of the products into enantioenriched 1,2‐diol
and 1,2‐aminoalcohol derivatives.
C Br
CC
C
OB
OB
O
O
(2.2 equiv)
10 mol % CuCl10 mol % Xantphos
K(O-t-Bu) (2.0 equiv)THF, 30 C, 4 h
C
CC
C
B
B88%
O
O
O
O
Borylative exo-Cyclization
Br
High exo/endo Selectivity
No Boryl Substitution
15
Scheme 11. Regio‐ and Enantioselective Borylation of (Z)‐Alkenylsilanes
Chapter 4 describes the the first example for enantioselective borylation of
a C=O double bond (Scheme 12).16 A series of aldehydes reacted with a
diboron compound in the presence of a copper(I)/DTBM‐SEGPHOS complex
catalyst using MeOH as a proton source to give the corresponding opticaly
active‐alkoxyorganoboronate esters with excellent enantioselectivies.
Scheme 12. Enantioselective Nucleophilic Borylation of Aldehydes
Chapter 5 describes density functional theory calculations were
performed to validate the proposed reaction mechanism for the
enantioselective nucleophilic borylation of a polarized C=O double bond in
the presence of diphosphine/borylcopper(I) complexes.17 Consequently, the
author successfully elucidated the origin for the regioselectivity and the
mechanism for the enantioselectivity of the reaction. The author also
obtained theoretical explanations for the fact that the presence of a proton
R H
O
R = Alkyl, ArylR H
B(pin)R3SiO5 mol % CuCl / L* B2(pin)2 (1.5 equiv)
K(O-t-Bu) (20 mol %)MeOH (2.0 equiv)THF then silylation
L* = (R)-DTBM-SEGPHOS
up to 82% yieldup to 99% ee
O
O
O
O
P
P
tBu
OMe
tButBu
OMetBu
2
2
Enantioselective Nucleophilic Borylation
16
source gave a higher reactivity and a better enantioselectivity in the
borylation reaction of aldehydes with a copper(I)/(R)‐DTBM‐SEGPHOS
complex catalyst.
Chapter 6 describes the first enantioselective borylative dearomatization
of indoles by copper(I) catalysis (Scheme 13).18 This reaction involves the
unprecedented regio‐ and enantioselective addition of active borylcopper(I)
species to indole‐2‐carboxylates, followed by the diastereoselective
protonation of the resulting copper(I) enolate to give the corresponding
chiral indolines bearing consecutive centers.
Scheme 13. Enantioselective Borylative Dearomatization of Indoles
Chapter 7 describes a novel approach to chiral 3‐borylpiperidines via the
copper(I)‐catalyzed regio‐ and enantioselective protoborylation of
1,2‐dihydropyridines derived from dearomative reduction of pyridine
derivatives (Scheme 14).19 This reaction involved the unprecedented regio‐
and enantioselective borylcupration of nitrogen containing cyclic conjugated
diene and subsequent protonation of resulting allylcopper(I) intermediate.
This dearomatization/enantioselective borylation sequence of readily
available aromatic compound pyridines provided a simple, mild and rapid
17
route to a variety of chiral piperidines, which are very important components
in various bioactive molecules and pharmaceutical drugs.
Scheme 14. Dearomatization/Enantioselective Borylation Stepwise Strategy
for Chiral Piperidine Synthesis
5 mol %CuCl / L*B2(pin)2
K(O-t-Bu)alcohol
N
R1
B(pin)
R2
abundantstarting material
N
R1 R2
N
R1 R2
R3O
O O
R3O
up to 96%, up to 99% eeup to d.r. 97:3, gram scale
N
N P
P
Me tBu
tBu Me
(R,R)-QuinoxP*
PPh2
PPh2
(R)-SEGPHOS
L* = or
Unprecedented Regio- and Enantioselective Borylation
18
References
(1) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Boronic
Acids: Preparation and Applications in Organic Synthesis, Medicine and
Materials, 2 nd revised ed.; Hall, D. G., Ed.; Wiley‐VCH: Weinheim,
2011.
(2) Reviews; (a) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111,
1417. (b) A. Rudolph, M. Lautens. Angew. Chem., Int. Ed. 2005, 44, 674.
(3) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature
2008, 456, 778. (b) Hupe, E.; Marek, I.; Knochel, P. Org. Lett. 2002, 4,
2861. (c) Crudden, C. M.; Glasspoole, B. W.; Lata, C. J. Chem. Commun.
2009, 6704.
(4) Hudron, Z. M.; Helander, M. G.; Lu, Z. –H.; Wan, S. Chem. Commun.
2011, 47, 755.
(5) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426.
(6) (a)Ishiyama, T.; Takagi, J. ; Ishida, K.; Miyaura, N.;
Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002 , 124 ,
390. (b) Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N.
J. Am. Chem. Soc. 2002 , 124 , 8001. (c) Ishiyama, T.; Takagi,
J. ; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002 ,
41 , 3056.
(7) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000,
41, 6821.
(8) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 29, 982.
(9) For copper(I)‐catalyzed borylation reactions from our group, see: (a)
Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034.
(b) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem.
Soc. 2007, 129, 14856. (c) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.;
Sawamura, M. Angew. Chem., Int. Ed. 2008, 47, 7424. (d) Ito, H.; Ito, H.;
Sasaki, Y.; Sasaki, Y.; Sawamura, M.; Sawamura, M. J. Am. Chem. Soc.
2008, 130, 15774. (e) Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J. Am.
19
Chem. Soc. 2010, 132, 1226. (f) Zhong, C.; Kunii, S.; Kosaka, Y.;
Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 11440. (g) Ito, H.;
Okura, T.; Matsuura, K.; Sawamura, M. Angew. Chem., Int. Edit. 2010,
49, 560. (h) Ito, H.; Toyoda, Sawamura, M. J. Am. Chem. Soc. 2010, 132,
5990. (i) Ito, H.; Kunii, S.; Sawamura, M. Naure. Chem. 2010, 2, 972. (j)
Sasaki, Y.; Sasaki, Y.; Horita, Y.; Horita, Y.; Zhong, C.; Zhong, C.;
Sawamura, M.; Sawamura, M.; Ito, H.; Ito, H. Angew. Chem., Int. Ed.
2011, 50, 2778.
(10) For selected examples of copper(I)‐catalyzed asymmetric borylation,
see: (a) Lee, J.‐E.; Lee, J.‐E.; Yun, J.; Yun, J. Angew. Chem., Int. Ed. 2008,
47, 145. (b) Lillo, V.; Prieto, A.; Bonet, A.; Diaz‐Requejo, M. M.;
Ramirez, J.; Perez, P. J.; Fernandez, E. Organometallics 2009, 28, 659. (c)
Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160. (d) Noh, D.;
Chea, H.; Ju, J.; Yun, J. Angew. Chem. Int. Ed. 2009, 48, 6062. (e) Chen,
I.‐H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 11664. (f) OʹBrien, J. M.; Lee, K.‐S.; Hoveyda, A. H. J. Am. Chem.
Soc. 2010, 132, 10630. (g) Moure, A. L.; Gómez Arrayás, R.; Carretero, J.
C. Chem Commun. 2011, 47, 6701. (h) Solé, C.; Solé, C.; Whiting, A.;
Whiting, A.; Gulyás, H.; Gulyás, H.; Fernandez, E.; Fernandez, E. Adv.
Synth. Catal. 2011, 353, 376. (i) Corberán, R.; Mszar, N. W.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2011, 50, 7079. (j) Lee, J. C. H.; McDonald, R.;
Hall, D. G. Nat. Chem. 2011, 3, 894. (k) Feng, X.; Feng, X.; Jeon, H.; Jeon,
H.; Yun, J.; Yun, J. Angew. Chem., Int. Ed. 2013, 52, 3989.
(11) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890.
(12) For related copper(I)‐catalyzed boryl substitution of organic halides:
Yang, C.‐T.; Zhang, Z.‐Q.; Tajuddin, H.; Wu, C.‐C.; Liang, J.; Liu, J.‐H.;
Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem.,
Int. Ed. 2011, 51, 528. (c) Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. B.
Angew. Chem., Int. Ed. 2009, 48, 5350.
(13) Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2013, 135, 2625.
(14) Kubota, K.; Yamamoto, E.; Ito, H. Adv. Synth. Catal. 2013, 355, 3527.
20
(15) Meng, F.; Jang, H.; Hoveyda, A. H. Chem. Euro. J. 2013, 19, 3204.
(16) Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 420.
(17) Kubota, K.; Mingoo, J.; Ito, H. Submitted.
(18) Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Angew. Chem., Int. Ed.
2015, 30, 8809.
(19) Kubota, K.; Watanabe, Y.; Hayama, K.; Ito, H. Submitted.
21
Chapter 1.
Copper(I)‐Catalyzed Direct Boryl Substitution of
Unactivated Alkyl Halides
22
Abstract
Borylation of Alkyl Halides with diboron proceeded in the presence of a
copper(I)/Xantphos catalyst and a stoichiometric amount of K(O‐t‐Bu) base.
The boryl substitution proceeded with normal and secondary alkyl chlorides,
bromides, and iodides, but alkyl sulfonates did not react. Menthyl halides
afforded the corresponding borylation product with excellent
diastereoselectivity, whereas (R)‐2‐bromo‐5‐phenylpentane gave a racemic
product. Reaction with cyclopropylmethyl bromide resulted in ring‐opening
products, suggesting the reaction involves a radical pathway.
Introduction
Organoboron compounds are indispensable synthetic reagents in organic
synthesis; much effort has therefore been devoted to the development of
efficient synthesis of organoborons.1–8 Although many excellent procedures
have been reported, boryl substitution of alkyl halides is still challenging. In
conventional procedures for organoboron synthesis, alkyl halides are the
starting materials for the organometallic nucleophiles, such as Grignard or
organolithium reagents, which react with boron electrophiles. This
procedure has significant limitations, especially in the presence of the
functional groups often found in structurally complex molecules. Direct
borylation of alkyl halides should be quite promising in this respect.
Yamashita and Nozaki recently created a boryllithium species by
introducing significant steric hindrance around the boryl atom (Scheme 1).3
Although this species has enough nucleophilicity to react with unactivated
alkyl halides, this elaborate reaction is not suitable for many common
organic syntheses.
23
Scheme 1. Synthesis of Boryllithium: Reactivity as a Boryl Anion
Miyaura and Marder also reported boryl substitutions of activated alkyl
halides such as allyl and benzyl chlorides; however, there are no general
borylation procedures for unactivated alkyl halides (Scheme 2).1,5a,b,7
Scheme 2. Transion‐Metal‐Catalyzed Boryl Substitution of Activated Alkyl
Halides
The author reports here the first practical method for boryl substitution
that is applicable to a broad range of alkyl halides with various functional
groups, offering a direct umpolung pathway for conventional reactions
based on carbon nucleophiles generated from alkyl halides.
Li, naphthalene
–LiBr
NB
NBr
BuCl
–LiCl
NB
NLi
NB
NBu
78%
Cl+ B B
O
O O
O Cat. B
O
O
with Pd cat./KOAc: Miyaura and Ishiyama (2002), 85%with Cu cat./K(O-t-Bu): T. B. Marder (2009), 61%
24
Results and Discussion
Recent advances in copper(I)‐catalyzed reactions with diboron
derivatives4–8 enable introduction of boryl groups into various organic
electrophiles such as αβ‐unsaturated carbonyl compounds,4a,5 allylic
esters,4b,c,f,g,6 aryl halides,7 allyl and benzyl halides,5a,b,7 and other
substrates.4d,h,i,j,k,8 The author did not anticipate that unactivated alkyl halides
could afford boron compounds by copper(I)‐catalyzed borylation because
previous studies found that alkyl sulfonates, which are good substrates for
nucleophilic substitutions, were resistant to direct boryl substitution.4h,9
In the course of the study, the author accidentally found that an alkyl
halide reacted with a diboron compound to produce the corresponding
alkylboronate in the presence of a copper(I) catalyst, which is very similar to
those our group previously reported.4b,h As shown in Table 1, entry 1, the
reaction between 2‐phenylethyl bromide 1a and bis(pinacolato)diboron 2
proceeded smoothly in the presence of a CuCl/Xantphos catalyst (3 mol%)
and a stoichiometric amount of K(O‐t‐Bu) base (1.0 equiv). The reaction was
complete within 4 h at room temperature and produced the corresponding
boronate 3a in high yield (94%) without any side‐product detection (Table 1,
entry 1). This catalysis requires a K(O‐t‐Bu) base, a copper(I) salt, and a
ligand, for the reaction to proceed (entries 2–4). Xantphos provided the best
result among the phosphine ligands tested; the reactions with PPh3, dppe
dppp, dppb, and dppf were slow and incomplete, resulting in moderate
yields of the product, even after long reaction times (entries 5–9). Use of a
copper(I)/NHC (NHC: N‐heterocyclic carbene) catalyst gave a much slower
initial reaction rate (entry 10). When a catalytic or stoichiometric amount of
Cu(O‐t‐Bu) was used instead of a CuCl/K(O‐t‐Bu) combination, only trace
amounts of the product were observed (entries 11 and 12). CuI, CuCN, and
Cu(OAc)2 can be used, but longer reaction times were required (entries 13–
15).10 A lower catalyst loading of 1 mol % also gave an excellent result (96%, 4
h, entry 16).
25
Table 1. Studies of Reaction Conditions for Copper(I)‐Catalyzed Boryl
Substitution of Alkyl Halides 1aa
This reaction was then evaluated for various alkyl halides, as summarized
in Table 2. Unactivated primary and secondary alkyl halides were converted
to the corresponding alkylboronates in good yield (entries 1–6). The effects of
the leaving group were investigated with cyclohexyl substrates (entries 2–5).
Reaction of cyclohexyl bromide 1d gave the borylation product 3c in the
highest yield, with a short reaction time (91%, 5 h), among cyclohexyl
chloride 1c and bromide 1e (72%, 18 h; 79%, 48 h, respectively). In contrast,
cyclohexyl mesylate 1f did not react (entry 5). This inreactivity is consistent
+O
BO
BO
O
2 (1.2 equiv)
3 mol % CuCl3 mol % Xantphos
base (1.0 equiv)THF, rt, 4 h
Br B(pin)
1a 3a
entry CuX ligand base yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CuCl
CuCl
none
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuClIPr
Cu(O-t-Bu) / 10 mol %
Cu(O-t-Bu) / 100 mol %
CuI
CuCN
Cu(OAc)2
CuCl / 1 mol %
Xantphos
Xantphos
Xantphos
none
PPh3
dppe
dppp
dppb
dppf
Xantphos / 10 mol %
Xantphos / 10 mol %
Xantphos
Xantphos
Xantphos
Xantphos / 1 mol %
K(O-t-Bu)
none
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
none
none
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
94
0
0
2
69
73
79
65
74
13
3
2
70
47
88
96
aConditions: 1a (0.5 mmol), CuX (0.015 mmol), ligand (0.015 mmol), K(O-t-Bu)/THF (1.0 M, 0.5 mL), 2 (0.6 mmol). bYield was determined by GC analysis of crude mixture with an internal standard. cCuClIPr: chloro [1,3-bis(2,6-diisopropylphenyl)-imidazole-2-ylidene]copper(I).
26
with our previous studies of related mesylate substrates.4h The reactions of
tertiary alkyl halides 1h and 1i were quite sluggish (entries 7 and 8). An
activated alkyl halide, benzyl bromide 1j, also gave the desired product in
moderate yield, accompanied by a small amount of a homo‐coupling
side‐product (1,2‐diphenylethane, 9%).7 This reaction proceeded in the
presence of various functional groups; acetal (1k), ester (1l), silyl ether (1m),
and sulfonate (1n) were compatible under these reaction conditions (entries
9–14). Alkylboronates bearing a ‐alkoxy group were not accessible by
Grignard or organolithium methods because the corresponding
organometallic compounds with a ‐alkoxy group could not be easily
prepared because they readily undergo ‐alkoxy elimination. This method
enables direct conversion of alkyl halide 1o to 3o (entry 14). Reactions of 1,1‐
and 1,3‐dibromo compounds proceeded smoothly to produce the
corresponding bis‐boryl products (entries 14 and 15). (1R,2R,4R)‐Menthyl
boronate 3r was synthesized with excellent diastereoselectivity (>99:1) from
both (1S,2R,5R)‐menthyl chloride 1r and (1S,2S,4R)‐neomenthyl bromide 1s
(entries 16 and 17, 85% and 81%, respectively). The reaction of the optically
active secondary alkyl halide (R)‐1t afforded the racemic product 3t (entry
19). These results indicate that the stereocenter originating from the chiral
C(sp3)–X bond undergoes rapid interconversion of configuration during the
reaction. This may cause epimerization to a thermodynamically stable
product (entries 17 and 18) and complete racemization (entry 19). This is
quite different from the results of our previous studies on
copper(I)‐catalyzed substitution of acyclic allylic carbonates with diboron,
where the anti‐SN2’ reaction proceeded with high stereospecificity.4b,11
27
Table 2. Copper(I)‐Catalyzed Boryl Substitution of Various Alkyl Halides
entry substrate product time (h) yield (%)b
Br B(pin) 4 85
X
1c, X = Cl1d, X = Br1e, X = I1f, X = OMs
B(pin)
185
4818
729179
0
1b 3b
3c
1
2345
B(pin)Br
1g 3g5 906
Br
1h7 44 0
Br B(pin)
8
1i 3i
48 17
Br B(pin)
1j 3j
9 5 51(59)
O
O
Br O
O
B(pin)1k 3k
10 5 86
O
O
Br
O
O
B(pin)1l 3l
11 24 80
TIPSO
Br
TIPSO
B(pin)1m 3m12 24 82
MsO
Br
MsO
B(pin)1n 3n13 6 80
28
This reaction does not include base‐promoted elimination/alkene
hydroboration pathway. The following experiments exclude this mechanism.
(1) Alkenes did not undergo hydroboration under the reaction conditions
presented in Table 1 and 2 (Scheme 3 and 4). (2) Base‐promoted elimination
of alkylhalides proceeded quickly in the presence of t‐BuOK; however, by
addition of 2, base‐promoted elimination was completely inhibited (Scheme
4). Complexation of t‐BuOK and Lewis acidic 2 would reduce the basicity of
t‐BuOK siginificantly. (3) Our boryl substitution of secondary alkyl halides
was regiospecific (Table 2, entries 6, 17, 18, and 19). However, elimination
products of secondary alkyl halides should give regio isomers in term of
aConditions: 1a (0.5 mmol), CuX (0.015 mmol), ligand (0.015 mmol), K(O- t-Bu)/THF (1.0M, 0.5 mL), 2 (0.6 mmol), room temparature. bIsolated yield. Values in parenthese are the yields determined by 1H NMR analysis of the crude reaction mixture. c5 mol % of catalyst and 1.2 equiv of K(O-t-Bu) were used. dReaction was conducted at 40 C with 15 mol % of catalyst and 2.2 equiv of 2. e2.0 equiv of K(O-t-Bu) was used. f10 mol % of catalyst and 2.0 equiv of 2 were used.
1o
14 6 51(65)O
Br
3o
OB(pin)
1p
15d,e 24 62
3pBr
Br
B(pin)
B(pin)
Br Br (pin)B B(pin)16d,e 30
1q 3q
68
Cl (pin)B
17f,e
18f,e
19c
Br (pin)B
1r 3r
1s 3s
31
30
85
81
Br B(pin)
(R)-1t, >99% ee (rac)-3t
24 93
29
double bond (Scheme 4). It is difficult to assume product convergence in
hydroboration of regio isomeric alkenes. In addition, the base‐promoted
elimination products from 1s and 1t did not underwent hydroboration under
the conditions for our copper(I)‐catalyzed boryl substitution of alkyl halides
(Scheme 4).
Scheme 3. Attempts of Copper(I)‐Catalyzed Hydroboration of Alkenes with
Diboron 2
Scheme 4. Experiments for Exclusion of Elimination/Hydroboration Pathway
of 1s and 1t
or
CuCl / Xantphos (3 mol %)
K(O-t-Bu) (1.0 equiv)THF, rt, 4 h
no reaction
Br
(pin)B-B(pin)(2.0 equiv)
THF, rt, 28 hXantphos(10 mol %)
K(O-t-Bu)(2.0 equiv)
+
< 1% (GC)
No E2 elimination
K(O-t-Bu)(2.0 equiv)
THF, rt, 37 h
+
57% (NMR) 28% (NMR)
CuCl / Xantphos (10 mol%)K(O-t-Bu) (2.0 equiv)(pin)B-B(pin) (2.0 equiv)THF, rt, 24 h
no reaction
No Hydroboration
Base-Promoted Elimination
In the absence of diboron 2
In the presenceof diboron 2
1s
30
In order to probe the reaction mechanism further, the author also carried
out the copper(I)‐catalyzed borylation of cyclopropylmethyl bromide (1u), as
illustrated in Scheme 5. 3‐Butenylboronate 4 (18%) and bis‐boryl product 5
(30%), which could be derived from 4 through further borylation of the
terminal double bond, were found in the reaction mixture, but the simple
boryl substitution product 3u was not detected. The formation of the
ring‐opening products suggests that this reaction could include a radical
pathway; this assumption is not inconsistent with the stereochemical
outcomes observed in entries 17–19, Table 2.12,13
Ph
Br(pin)B-B(pin)(1.2 equiv)
THF, rt, 20 hXantphos(5 mol %)
K(O-t-Bu)(1.2 equiv)
No E2 elimination
K(O-t-Bu)(1.2 equiv)
THF, rt, 20 h
51% (NMR)
34% (NMR)
CuCl / Xantphos (5 mol%)K(O-t-Bu) (1.2 equiv)(pin)B-B(pin) (1.2 equiv)THF, rt, 20 h
no reaction
No Hydroboration
Ph
Ph
< 1% (GC)
< 1% (GC)
Ph
Ph
Base-Promoted Elimination
In the absence of diboron 2
In the presenceof diboron 2
1t
31
Scheme 5. Copper(I)/Xantphos‐Catalyzed Borylation of Cyclopropylmethyl
bromide (1u)
The proposed reaction mechanism of the current borylation reaction is
shown in Scheme 6. First, copper(I) salt A reacts with K(O‐t‐Bu) base and a
diboron compound to form active species B. The single electron transfer
between a borylcopper(I) and alkylhalide occurs to generate copper(II)
intermediate D and alkyl redical species. Further single electron transfer
proceeds to give the copper(III) complex E and then subsequent reductive
elimination provides the corresponding boryl substituted product and
copper(I) halide A.
Scheme 6. Proposed Reaction Mechanism
Br
CuCl / Xantphos (3 mol%)K(O-t-Bu) (1.0 equiv)2 (1.2 equiv)
THF, rt, 24 h
B(pin) (pin)BB(pin)+
unidentified products
4, 18% (NMR) 5, 30% (NMR)
+
1u
B(pin)
3u, 0%
LCu B(pin)I RBr Br
LCu B(pin)I
R
Br
LCu
B(pin)
II RBr
LCuIII
LCu XI
B(pin)R
+ K(O-t-Bu)+ (pin)B-B(pin)
B(pin)
R
L = Xantphos
X = Cl or Br
A
B
C
DE
32
Conclusion
In summary, the auther have developed a novel copper(I)‐catalyzed
reaction as the first practical procedure for boryl substitution of unactivated
alkyl halides. This reaction offers a direct umpolung pathway for the
conventional carbon nucleophile method, and has high functional group
compatibility and interesting stereochemical‐controlling properties. The
author believes that this procedure will be a powerful synthetic method for a
broad range of alkylboronates, including those that could not be synthesized
by previous methods.
33
Experimental
General.
Materials were obtained from commercial suppliers and purified by the
standard procedure unless otherwise noted. Solvents were purchased from
commercial suppliers, degassed via three freeze‐pump‐thaw cycles, and
further dried on MS 4A. NMR spectra were recorded on JEOL JNM‐ECX400P
spectrometer (1H: 400 MHz and 13C: 100 MHz).Tetramethylsilane (1H) and
CDCl3 (13C) were employed as external standards, respectively. CuCl
(ReagentPlus® grade, 224332‐25G, ≥99%) and K(O‐t‐Bu)/THF (1.0 M,
328650‐50ML) were purchased from Sigma‐Aldrich Co. and used as received.
Mesitylene or 1,1,2,2‐tetrachloroethane was used as the internal standard for
determining NMR yield. GLC analysis was conducted with Shimadzu
GC‐2014 or GC‐2025 equipped with ULBON HR‐1 glass capillary column
(Shinwa Chemical Industries) and a FID detector HPLC analyses with chiral
stationary phase were carried out using Hitachi LaChrome Elite HPLC
system with L‐2400 UV detector. Recycle preparative gel permeation
chromatography was conducted with JAI LC‐9101 using CHCl3 as the eluent.
Low‐ and High‐resolution mass spectra were recorded at the Center for
Instrumental Analysis, Hokkaido University.
Experimental.
Starting Materials.
1f and 1n were prepared from the corresponding alcohols and
methanesulfonyl chloride by a standard procedure. 1l and 1m were
synthesized from the 5‐bromopentanol by standard esterification and
silylation procedures. 1s was synthesized by bromination of (–)‐menthol with
CBr4/PPh3 reagents.15 Other alkyl halide substrates were purchased from
commercial suppliers. The purchased starting materials were not subjected to
further purification but dried over MS4A before use.
34
Representative Procedure for Borylation.
Cooper chloride (1.5 mg, 0.015 mmol) and bis(pinacolato)diboron (152.4 mg,
0.6 mmol), Xantphos (8.7 mg, 0.015 mmol) were placed in an oven‐dried
reaction vial. The vial was sealed with a screw cap containing a Teflon‐coated
rubber septum. The vial was connected to a vacuum/nitrogen manifold
through a needle, evacuated and backfilled with nitrogen. THF (0.5 mmol)
and K(O‐t‐Bu)/THF (1.0 M, 0.25 mL, 0.25 mmol) were added in the vial
through the rubber septum. Then alkyl halide 1 (0.5 mmol) was added
dropwise. After the reaction was complete, the reaction mixture was passed
through a short silica column eluting with ethyl acetate/hexane (10:90). The
crude mixture was further purified by flash column chromatography (SiO2,
ethyl acetate/hexane, 0.5:99.5–2.5:97.5). The flash column chromatography is
completed within 10 min. to minimize decomposition of the product.
4,4,5,5‐Tetramethyl‐2‐phenethyl‐1,3,2‐dioxaborolane (3a).16
1H NMR (400 MHz, CDCl3, δ): 1.14 (t, J = 8.2 Hz, 2H), 1.22 (s, 12H), 2.75 (t, J =
8.4 Hz, 2H), 7.13–7.29 (m, 5H). 13C NMR (100 MHz, CDCl3, δ): 13.0 (br, B–
CH2), 24.7 (CH3), 29.9 (CH2), 83.0 (C), 125.4 (CH), 127.9 (CH), 128.1 (CH),
144.3 (C). HRMS–EI (m/z): [M]+ calcd for C14H21BO2, 232.1636; found,
232.1635. Anal. Calcd for C14H21BO2: C, 72.44; H, 9.12. Found: C, 72.68; H,
9.31.
35
4,4,5,5‐Tetramethyl‐2‐cyclohexyl‐1,3,2‐dioxaborolane (3b).17
1H NMR (400 MHz, CDCl3, δ):0.94–1.05 (m, 1H), 1.24 (s, 12H), 1.25–1.39 (m,
4H), 1.59–1.67 (m, 6H). 13C NMR (100 MHz, CDCl3, δ): 22.0 (br, B–CH2), 24.7
(CH3), 26.7 (CH2), 27.1 (CH2), 27.9 (CH2), 82.6 (C). HRMS–EI (m/z): [M]+
calcd for C12H23BO2, 210.1791; found, 210.1802.
4,4,5,5‐Tetramethyl‐2‐butyl‐1,3,2‐dioxaborolane (3c).18
1H NMR (400 MHz, CDCl3, δ): 0.78 (t, J = 7.8 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H),
1.24 (s, 12H), 1.28–1.43 (m, 4H). 13C NMR (100 MHz, CDCl3, δ): 10.5 (br, B–
CH2), 13.8 (CH3), 24.7 (CH3), 25.4 (CH2), 26.2 (CH2), 82.8 (C). HRMS–EI
(m/z): [M]+ calcd for C10H21BO2, 184.1635; found, 184.1644.
2‐cyclopentyl‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (3d).
1H NMR (400 MHz, CDCl3, δ): 1.13‐1.19 (m, 1H), 1.24 (s, 12H), 1.40‐1.54 (m,
4H), 1.58‐1.64 (m, 2H), 1.71‐1.80 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): 21.8
(br, B–CH), 24.6 (CH3), 26.8 (CH2), 28.4 (CH2), 82.7 (C). HRMS–EI (m/z):
[M‐CH3]+ calcd for C10H18BO2, 181.13998; found, 181.13998.
36
2‐cyclobutyl‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (3e).
1H NMR (400 MHz, CDCl3, δ): 1.26 (s, 12H), 1.88‐2.12 (m, 7H). 13C NMR
(100 MHz, CDCl3, δ): 17.9 (br, B–CH), 22.6 (CH2), 23.8 (CH2), 24.7 (CH3), 82.8
(C). HRMS–EI (m/z): [M‐CH3]+ calcd for C9H16BO2, 167.12422; found,
167.12445.
4,4,5,5‐Tetramethyl‐2‐(2‐phenylpopan‐2‐yl)‐1,3,2‐dioxaborolane (3f).19
1H NMR (400 MHz, CDCl3, δ): 0.96 (d, J = 7.3 Hz, 3H), 1.19 (s, 12H), 1.37 (q, J
= 7.8 Hz, 1H), 2.54 (dd, J = 8.7 and 13.7 Hz, 1H), 2.81 (dd, J = 7.8 and 13.7 Hz,
1H), 7.13–7.26 (m, 5H). 13C NMR (100 MHz, CDCl3, δ): 15.1 (CH3), 19.5 (br, B–
CH), 24.6 (CH3), 38.9 (CH2), 82.9 (C), 125.5 (CH), 127.9 (CH), 128.8 (CH), 142.2
(C). HRMS–EI (m/z): [M]+ calcd for C15H23BO2, 246.1791; found, 246.1791.
2‐Adamantyl‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (3h).
1H NMR (400 MHz, CDCl3, δ): 1.21 (s, 12H), 1.73–1.77 (br, 12H), 1.82–1.87 (br,
3H). 13C NMR (100 MHz, CDCl3, δ): 24.6 (CH3), 27.5 (CH), 37.5 (CH2), 37.9
37
(CH2), 82.6 (C). The carbon directly attached to the boron atom was not
detected, likely due to quadropolar relaxation. HRMS–EI (m/z): [M]+ calcd for
C16H27BO2, 262.2104; found, 262.2109.
2‐Benzyl‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (3i).20
1H NMR (400 MHz, CDCl3, δ): 1.23 (s, 12H), 2.29 (s, 2H), 7.09–7.25 (m, 5H).
13C NMR (100 MHz, CDCl3, δ): 20.0 (br, B–CH2), 24.7 (CH3), 83.3 (C), 124.8
(CH), 128.2 (CH), 128.9 (CH), 138.6 (C). HRMS–EI (m/z): [M]+ calcd for
C13H19BO2, 218.1478; found, 218.1478.
1,1‐Bis(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)ethane (3j).21
1H NMR (400 MHz, CDCl3, δ): 0.73 (q, J = 7.4 Hz, 1H), 1.05 (d, J = 7.7 Hz, 3H),
1.227 (s, 12H), 1.234 (s, 12H). 13C NMR (100 MHz, CDCl3, δ): 0.2 (br, B–CH2),
9.0 (CH3), 24.5 (CH3), 24.5 (CH3), 82.8 (C). HRMS–EI (m/z): [M]+ calcd for
C14H28B2NaO4, 305.2067; found, 305.2066.
1,1‐Bis(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)propane (3k).
3k
B BO
OO
O
38
1H NMR (400 MHz, CDCl3, δ): 0.81 (t, J = 8.1 Hz, 4H), 1.24 (s, 24H), 1.54
(quint, J = 8.1 Hz,
2H). 13C NMR (100 MHz, CDCl3, δ): 14.0 (br, B–CH2), 18.5 (CH2), 24.7 (CH3),
82.7 (C). HRMS–EI (m/z): [M+Na]+ calcd for C15H30B2NaO4, 319.2228; found,
319.2223.
2‐(2‐(1,3‐Dioxan‐2‐yl)ethyl)‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (3l).
1H NMR (400 MHz, CDCl3, δ): 0.83 (t, J = 7.9 Hz, 2H), 1.23 (s, 12H), 1.28–1.36
(m, 1H), 1.72 (dt, J = 7.7 and 5.1 Hz, 2H), 2.00–2.12 (m, 1H), 3.774 (m, 2H), 4.1
(m, 2H), 4.47 (t, J = 5.1 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 5.3 (br, B–
CH2), 24.6 (CH3), 25.7 (CH2), 29.3 (CH2), 66.6 (CH2), 82.7 (C), 102.9 (CH).
HRMS–EI (m/z): [M–H]+ calcd for C12H22BO4, 241.1611; found, 241.1619.
Anal. Calcd for C12H23BO4: C, 59.53; H, 9.57. Found: C, 59.77; H, 9.67.
5‐(4,4,5,5‐Tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pentyl pivalate (3m).
1H NMR (400 MHz, CDCl3, δ): 0.79 (t, J = 7.7 Hz, 2H), 1.19 (s, 9H), 1.24 (s,
12H), 1.32–1.49 (m, 4H), 1.59–1.66 (m, 2H), 4.04 (t, J = 6.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3, δ): 10.5 (br, B–CH2), 23.5 (CH2), 24.7 (CH3), 27.1 (CH3),
28.3 (CH2), 28.5 (CH2), 38.5 (C), 64.3 (CH2), 82.7 (C), 178.4 (C). HRMS–EI
(m/z): [M]+ calcd for C16H31BNaO4, 321.2208; found, 321.2208.
39
4,4,5,5‐Tetramethyl‐5‐tri(isopropyl)silyloxy‐1,3,2‐dioxaborolane (3n).
1H NMR (400 MHz, CDCl3, δ): 0.78 (t, J = 7.9 Hz, 2H), 1.02–1.13 (m, 21H),
1.24 (s, 12H), 1.30–1.47 (m, 4H), 1.50–1.59 (m, 1H), 3.66 (t, J = 6.9 Hz, 2H). 13C
NMR (100 MHz, CDCl3, δ): 11.1 (br, B–CH2), 11.9 (CH), 18.0 (CH3), 23.9
(CH2), 24.7 (CH3), 28.6 (CH2), 32.9 (CH2), 63.5 (CH2), 82.8 (C). HRMS–EI
(m/z): [M–CH3]+ calcd for C19H40BO3Si, 355.2840; found, 355.2843. Anal.
Calcd for C20H43BO3Si: C, 64.84; H, 11.70. Found: C, 64.66; H, 11.88.
5‐(4,4,5,5‐Tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pentyl methanesulfonate
(3o).
1H NMR (400 MHz, CDCl3, δ): 0.79 (t, J = 7.5 Hz, 2H), 1.23 (s, 12H), 1.34–1.48
(m, 4H), 1.75 (quint, J = 7.1 Hz, 2H), 3.00 (s, 3H), 4.20 (t, J = 6.8 Hz, 2H). 13C
NMR (100 MHz, CDCl3, δ): 10.9 (br, B–CH2), 23.3 (CH2), 24.7 (CH3), 27.8
(CH2), 28.7 (CH2), 37.2 (CH3), 70.1 (CH2), 82.8 (C). HRMS–EI (m/z): [M+Na]+
calcd for C12H25BNaO5S, 315.1413; found, 315.1408. Anal. Calcd for
C12H25BO5S: C, 49.33; H, 8.62. Found: C, 49.35; H, 8.64.
4,4,5,5‐Tetramethyl‐2‐(2‐phenoxyethyl)‐1,3,2‐dioxaborolane (3p).
1H NMR (400 MHz, CDCl3, δ): 1.26 (s, 12H), 1.37 (t, J = 7.9 Hz, 2H), 4.11 (t, J =
8.0 Hz, 2H), 6.89–6.94 (m, 3H), 7.24–7.29 (m, 2H). 13C NMR (100 MHz, CDCl3,
3n
OSi
BO
O
3p
OB
O
O
40
δ): 12.3 (br, B–CH2), 24.7 (CH3), 64.7 (CH2), 83.3 (C), 114.5 (CH), 120.3 (CH),
129.3 (CH), 159.0 (C). HRMS–EI (m/z): [M]+ calcd for C14H21BO3, 248.1584;
found, 248.1579.
2‐[(1R,2R,5R)‐2‐Isopropyl‐5‐methylcyclohexyl]‐4,4,5,5‐tetramethyl‐1,3,2‐dio
xaborolane (3r).
1H NMR (400 MHz, CDCl3, δ): 0.72–1.00 (m, 4H), 0.77 (d, J = 6.9 Hz, 3H), 0.84
(d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 1.21–1.32 (m, 14H), 1.56–1.72 (m,
4H). 13C NMR (100 MHz, CDCl3, δ): 16.4 (CH3), 21.6 (CH3), 22.7 (CH3), 24.6
(CH3), 24.7 (CH3), 25.8 (CH2), 28.0 (br, B‐CH), 32.0 (CH), 33.4 (CH), 35.3
(CH2), 37.1 (CH2), 43.7 (CH), 82.6 (C). HRMS–EI (m/z): [M]+ calcd for
C16H31BO2, 266.2417; found, 266.2415. Anal. Calcd for C16H31BO2: C, 72.18; H,
11.74. Found: C, 72.31; H, 11.74. [α]D 20.5 –2.00 (deg cm3 g‐1 dm‐1) (c 0.0583 in
CHCl3).
4,4,5,5‐Tetramethyl‐2‐(5‐phenylpentan‐2‐yl)‐1,3,2‐dioxaborolane (3t).
1H NMR (400 MHz, CDCl3, δ): 0.96 (d, J = 7.0 Hz, 3H), 1.00–1.09 (m, 1H),
1.23 (s, 12H), 1.30–1.39 (m, 1H), 1.47–1.56 (m, 1H), 1.59–1.69 (m, 2H), 2.60 (t, J
= 7.9 Hz, 2H), 7.14–7.18 (m, 3H), 7.25–7.28 (m, 2H). 13C NMR (100 MHz,
CDCl3, δ): 15.4 (CH3), 16.8 (br, B–CH), 24.6 (CH3), 24.7 (CH3), 30.8 (CH2),
32.9 (CH2), 36.1 (CH2), 82.7 (C), 125.4 (CH), 128.1 (CH), 128.3 (CH), 142.8 (C).
41
HRMS–EI (m/z): [M]+ calcd for C17H27BO2, 274.2104; found, 274.2104.
1,4‐Bis(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)butane (5)
1H NMR (400 MHz, CDCl3, δ): 0.77 (t, J = 7.3 Hz, 4H), 1.24 (s, 24H), 1.39–1.42
(m, 4H). 13C NMR (100 MHz, CDCl3, δ): 10.8 (br, B–CH2), 24.8 (CH3), 26.9
(CH2), 82.8 (C). [M–CH3]+ calcd for C15H29B2O4, 295.2252; found, 293.2250.
BB
5
O
O
O
O
42
References and Notes
(1) (a) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, Second, Revised, Edition; Hall, D. G., Ed.; Wiley‐VCH:
Weinheim, 2011. (b) Matteson, D. S. Stereodirected Synthesis with
Organoboranes; Springer: Berlin, 1995. (c) Boron Compounds, Science of
Syntheses; Kaufmann, D., Ed.; Georg Thieme Verlag: Stuttgart, 2005; Vol. 6.
(d) Chemler, S. R.; Roush, R. W. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley‐VCH: Weinheim, 2000, p 403–490. (e) Miyaura, N; Yamamoto, Y. In
Comprehensive Organometallic Chemistry III, Ed.; Crabtree R. H.; Mingos, M. P.;
Elsevier: Amsterdam, 2007, Vol. 9, p 146–244.
(2) For selected reviews of transition‐metal‐catalyzed reactions, see: (a)
Crudden, C. M.; Edwards, D. Chem. Eur. J. 2003, 4695. (b) Miyaura, N. Bull.
Chem. Soc. Jpn. 2008, 81, 1535. (c) Dang, L.; Lin, Z. Y.; Marder, T. B. Chem.
Commun. 2009, 3987.
(3) (a) Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113. (b)
Kajiwara, T.; Terabayashi, T.; Yamashita, M.; Nozaki, K. Angew. Chem., Int. Ed.
2008, 47, 6606. (c) Okuno, Y.; Yamashita, M.; Nozaki, K. Angew. Chem., Int. Ed.
2011, 50, 920. (d) Yamashita, M. Bull. Chem. Soc. Jpn. 2011, 84, 983.
(4) Copper(I)‐catalyzed reaction of diboron developed by Ito and
Sawamura group, see: (a) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A.
Tetrahedron Lett. 2000, 41, 6821. (b) Ito, H.; Kawakami, C.; Sawamura, M. J.
Am. Chem. Soc. 2005, 127, 16034. (c) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.;
Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (d) Ito, H.; Kosaka, Y.;
Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47, 7424.
(e) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774. (f) Ito,
H.; Kunii, S.; Sawamura, M. Nature Chem. 2010, 2, 972. (g) Ito, H.; Okura, T.;
Matsuura, K.; Sawamura, M. Angew. Chem., Int. Ed. 2010, 49, 560. (h) Ito, H.;
Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990. (i) Sasaki, Y.;
Zhong, C. M.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226. (j)
Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010,
43
132, 11440. (k) Sasaki, Y.; Horita, Y.; Zhong, C. M.; Sawamura, M.; Ito, H.
Angew. Chem., Int. Ed. 2011, 50, 2778.
(5) Selected examples of copper(I)‐catalyzed reactions of ,‐unsaturated
carbonyl compounds, see: (a) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem.
Lett. 2000, 982. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet.
Chem. 2001, 625, 47. (c) Mun, S.; Lee, J.; Yun, J. Org. Lett. 2006, 8, 4887. (d) Lee,
J.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145. (e) Bonet, A.; Lillo, V.; Ramirez,
J.; Diaz‐Requejo, M.; Fernandez, E. Org. Biomol. Chem. 2009, 7, 1533. (f) Chea,
H.; Sim, H.; Yun, J. Adv. Synth. Catal. 2009, 351, 855. (g) Chen, I.‐H.; Yin, L.;
Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 11664. (h)
O’Brien, J. M.; Lee, K.‐s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10630. (i)
Gao, M.; Thorpe, S. B.; Santos, W. L. Org. Lett. 2009, 11, 3478. See also: ref. 4a.
(6) (a) Guzman‐Martinez, A.; Hoveyda, A. J. Am. Chem. Soc. 2010, 132,
10634. (b) Park, J.; Lackey, H.; Ondrusek, B.; McQuade, D. J. Am. Chem. Soc.
2011, 133, 2410.
(7) Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. Angew. Chem., Int. Ed. 2009, 48,
5350.
(8) Other selected examples of copper(I)‐catalyzed reactions, see: (a) Laitar,
D.; Muller, P.; Sadighi, J. J. Am. Chem. Soc. 2005, 127, 17196. (b) Laitar, D.; Tsui,
E.; Sadighi, J. J. Am. Chem. Soc. 2006, 128, 11036. (c) Lee, Y.; Jang, H.; Hoveyda,
A. J. Am. Chem. Soc. 2009, 131, 18234. (d) McIntosh, M.; Moore, C.; Clark, T.
Org. Lett. 2010, 12, 1996.
(9) Our group previously reported that a 4‐silyl‐3‐butenyl
methanesulfonate gave a cyclobutylboronate product under
copper(I)‐catalyzed conditions in the presence of diboron, in which no simple
substitution product was detected.
(10) Copper(II) salt was most probably reduced to copper(I) at the initial
step of the catalysis. See also ref. 6a.
(11) Stereochemistry of alkylation with copper(I) reagents, see: (a)
Whitesides, G. M.; Fischer, W. F.; San Filippo, J.; Bashe, R. W.; House, H. O. J.
Am. Chem. Soc. 1969, 91, 4871. (b) Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc.
44
1973, 95, 7777. (c) Lipshutz, B.; Wilhelm, R. S. J. Am. Chem. Soc. 1982, 104, 4696.
(d) Mori, S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, 7294.
(e) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew. Chem.,
Int. Ed. 2007, 46, 2086.
(12) For radical pathways in reactions of lithium organocuprate with alkyl
halides, see: (a) Ashby, E. C.; DePriest, R. N.; Tuncay, A.; Srivastava, S.
Tetrahedron Lett. 1982, 23, 5251. (b) Ashby, E. C.; Coleman, D. J. Org. Chem.
1987, 52, 4554.
(13) For rapid isomerization of a cyclopropyl radical to the butenyl radical,
see: (a) Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem. Soc. 1976, 98, 7024.
(b) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
(14) During investigation of this reaction, a similar borylation with
CuI/PPh3 catalytic system was published. Yang, C.‐T.; Zhang, Z.‐Q.; Tajuddin,
H.; Wu, C.‐C.; Liang, J.; Liu, J.‐H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marde,
T. B.; Liu, L. Angew. Chem., Int. Ed. 2011, 51, 528.
(15) Goldenstein, K.; Fendert, T.; Proksch, P.; Winterfeldt, E. Tetrahedron 2000,
56, 4173.
(16) Cano, R.; Ramón, D. J.; Yus, M. J. Org. Chem. 2010, 75, 3458.
(17) Blakemore, P. R.; Burge, M. S. J. Am. Chem. Soc. 2007, 129, 3068.
(18) Yamamoto, Y.; Fujikawa, R.; Umemoto, T.; Miyaura, N. Tetrahedron 2004,
60, 10695.
(19) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160.
(20) Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem., Int. Ed. 2009,
48, 5350.
(21) Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem. 2010, 75, 3469.
45
Chapter 2.
Copper(I)‐Catalyzed Intramolecular Borylative
exo‐Cyclization of Alkenyl Halides Containing
Unactivated Double‐Bond
46
Abstract
A borylative exo‐cyclization of alkenyl halides has been reported. The
reaction includes the regioselective addition of a borylcopper(I) intermediate
to unactivated terminal alkenes, followed by the intramolecular substitution
of the resulting alkylcopper(I) moiety for the halide leaving groups.
Experimental and theoretical investigations of the reaction mechanism have
also been described. This reaction provides a new method for the synthesis of
alkylboronates containing strained cycloalkyl structures from simple starting
materials.
Introduction
Organoboron compounds are very important synthetic reagents and their
efficient preparation has attracted considerable levels of attention over the
years.1 The hydroboration of alkenes is an established method for
alkylborane synthesis. When the hydroboration of a carbon‐carbon double
bond occurs with concomitant CC bond formation, this can be highly
beneficial for the efficient construction of various alkylboronates.
Furthermore, the products of these reactions invariably possess more
complex structures than those that could be obtained via conventional
hydroboration chemistries or other classical methods involving carbon
nucleophiles. In spite of these potential benefits, reactions based on this
concept of 1,2‐carboboration have been scarcely reported in the literature
(Figure 1).2–6
47
Figure 1. Two Types of Borylation Reaction of CC Double Bond by using
Borylcopper(I) Spicies
Ito and Sawamura group previously reported copper(I)‐catalyzed
borylative cyclizations as an example of a borylation process involving a CC
bond formation (Scheme 1a).7–9 These reactions included the regioselective
addition of the borylcopper(I) to alkene, which was facilitated by an
electronic directing group (Y). The subsequent intramolecular substitution
afforded a variety of different cycloalkyl boronates as the endo‐cyclization
products. Herein, the author reports a new borylative cyclization reaction
involving the unprecedented regioselective addition of a borylcopper(I)
intermediate to an unactivated terminal double bond, followed by
intermolecular cyclization to produce the exo‐cyclization product (Scheme
1b).9,10 The resulting products have interesting carbocyclic structure with a
borylmethyl moiety. Derivatizations of the product using the boryl group,
such as oxidation, amination, homologation and Suzuki‐Miyaura coupling,
were conducted to demonstrate the synthetic utility of this reaction.
Experimental and theoretical investigations of the reaction mechanism have
also been described.
C
C
B
Cu
C
CB
Cu
C
C
B
H
H+
C X
C
C
B
C
Hydroboration
Carboboration
Alkylcopper(I)Intermediate
48
Scheme 1. Copper(I)‐Catalyzed Intramolecular Borylative Cyclization of
Alkenes
Results and Discussion
In all of the previous reports concerning the copper(I)‐catalyzed borylation
of carbon‐carbon double bonds, electronically activated substrates have been
used (i.e. substrates with a low LUMO level capable of effectively interacting
with the borylcopper(I) HOMO).7,8,11,12 For reported previous cyclization
reactions, a silyl or an aryl group (Y) was required to promote the reaction
and provide a high level of regioselectivity (Scheme 1a).7 There have been no
reports for the reaction between the borylcopper(I) intermediate and
unactivated alkenes such as 1‐hexene.11,13 To design a new carboboration
process, the author initially checked this preconceived reactivity profile
(Table 1). Pleasingly, the reaction between 1‐hexene (1a) with
bis(pinacolato)diboron (2) in the presence of a Cu(O‐t‐Bu)/Xantphos catalyst
system with MeOH as a proton source proceeded smoothly to afford the
monoborylation product 3a in excellent yield with good regioselectivity (3a,
81%; 3a’, 7%) (Table 1, entry 1). The same reaction proceeded well with the
more readily available CuCl/Xantphos/K(O‐t‐Bu) catalytic system (entry 2).
Previous Work: Endo-Cyclization
C C
Y X
n = 13Y = R3Si, Ar, HetAr; X = OCO2R, OMs, OPO(OR)2
Cu cat.
B Bn
C C
Y X
Cu B
CuXC C
B
Y n
This Work: Exo-Cyclization
C C X
nn = 13, X = Br
Cu cat.
B B
C C
n X
CuB
CuX C CB
n
a)
b)
49
The use of MeOD instead of MeOH gave the 2‐deuterated product that
corresponded to the trapping product of the alkylcopper(I) intermediate
(entry 3). In contrast, the use of PPh3 or N‐heterocyclic carbenes (NHC) in the
same reaction instead of Xantphos gave poor results without detection of
β‐hydride elimination products (entries 4–6). Interestingly, the investigation
of a reaction using the internal alkene, 2‐hexene, resulted only in failure even
when the Xantphos ligand was used (entry 7).
Table 1. Copper(I)‐Catalyzed Monoborylation of Unactivated Alkenes
With a new procedure in hand for the regioselective addition of
borylcopper(I) to terminal double bonds, the author proceeded to investigate
the exo‐cyclization process (Table 2). The desired product 5a was exclusively
+ B BO
OO
O
copper(I) catalyst (5 mol %)K(O-t-Bu) (1.2 equiv)
THF, 30 C, 24 h
+H(D)
(pin)BB(pin)
(HD)
+ MeOH or MeOD (2.0 equiv)
entry copper(I) catalyst
1a2 (1.2 equiv)
3a 3a'
3a (%)b 3a' (%)b
1c
2
3d
4
5e
6e
7f
Cu(O-t-Bu)/Xantphos
CuCl/Xantphos/K(O-t-Bu)
CuCl/Xantphos/K(O-t-Bu)
CuCl/PPh3/K(O-t-Bu)
CuCl/IPr/K(O-t-Bu)
CuCl/IMes/K(O-t-Bu)
CuCl/Xantphos/K(O-t-Bu)
81
91
92 (>95% D)
14
1
12
trace
7
7
6
3
7
16
0
aConditions: 1 (0.5 mmol), CuCl (0.025 mmol), ligand (0.025 mmol), K(O-t-Bu)/THF (0.6 M, 1.0 mL), 2 (0.6 mmol), MeOH (1.0 mmol). bYield was determined by GC analysis of the crude mixture with an internal standard. cCu(O-t-Bu) (0.025 mmol) was used. dMeOD (1.0 mmol) was used. eIPr: 1,3-bis(2,6-diisopropylphenyl)imidazolium. IMes: 1,3-bis(2,4,6-trimethylphenyl)imidazolium. f2-Hexene was used instead of 1-hexene.
50
produced from 4a in excellent yield (entries 1 and 2) when chloride or
bromide was used as the leaving group and the ligand was Xantphos.
Although alkyl halides lacking a terminal double bond are good substrates
for the copper(I)‐catalyzed boryl substitution reaction, in this reaction, none
of the simple boryl substitution product was detected.9 Alkenyl iodide and
tosylate were converted into an isomeric mixture of 5a and 6a (entries 3 and
4). The author next investigated the ligand effect (entries 5–13). In the
absence of a ligand, the reaction did not proceed to completion (entry 5). In
the presence of the monophosphine ligands, the reactions tended to produce
the boryl substitution product 6a rather than the cyclization product 5a
(entries 6–9). When the reaction was conducted in the presence of rigid
diphosphine ligands (Xantphos, dppf), they showed a preference for the
cyclization reaction (enties 1–4, 13). Use of a stoichiometric amount of
Cu(O‐t‐Bu) instead of CuCl/K(O‐t‐Bu) resulted in almost no reaction (entry
14), indicating that K(O‐t‐Bu) is needed for the cyclization step.
The author also tested the construction of cyclobutane frameworks
through the borylative exo‐cyclization (Scheme 2). 5‐Bromopentene (4b) was
successfully converted into the cyclobutylmethylboronate 5b in good yield
(88%) with excellent chemoselectivity (6b, <1%). In a similar manner to the
cyclopropanation case, the cyclization/substitution selectivity could be
switched when P(C6F5)3 was used as the ligand (5b/6b = 12:88).
51
Table 2. Copper(I)‐Catalyzed Borylative Cyclization and Substitution
Reactions of Alkenyl Halides and Pseudo Halides 4aa
Scheme 2. Borylative Cyclization of 5‐Bromopentene (4b)
CuCl / ligand (5 mol %)K(O-t-Bu) (1.2 equiv)
2 (1.2 equiv)THF, 30 C, 24 h
entry ligand
5a 6a
5a (%)b 6a (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
Xantphos
Xantphos
Xantphos
Xantphos
none
PPh3
P(C6F5)3
P(OPh)3
PBu3
dppe
dppp
dppb
dppf
Xantphos
99
99
38
65
15
15
6
6
11
32
47
9
87
<1
<1
<1
42
27
7
35
45
32
31
33
24
47
4
4
aConditions: 4a (0.5 mmol), CuCl (0.025 mmol), ligand (0.025 mmol), K(O-t-Bu)/THF (0.6 M, 1.0 mL), 2 (0.6 mmol). bYield was determined by GC analysis of the crude mixture with an internal standard. cCu(O-t-Bu) (0.025 mmol) was used instead of CuCl/K(O-t-Bu).
X
4aB
O
O+ B
O
O
X
Cl
Br
I
OTs
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
4b
+
2 (1.2 equiv)
CuCl / Xantphos (5 mol %)K(O-t-Bu) (1.2 equiv)
THF, 30 C, 24 h
CuCl / P(C6F5)3 (5 mol %)K(O-t-Bu) (1.2 equiv)
THF, 30 C, 24 h
(pin)B
5b, 88%
B(pin)
6b, 46%
+ 6b
<1%
+ 5b
7%
52
The synthesis of a variety of different cyclic compounds was then
investigated (Table 3). The reactions of secondary alkenyl bromides (4c and
4d) proceeded smoothly to give the corresponding cyclopropylmethy
boronates (5c, 94% and 5d, 92%, respectively; cyclization/substitution = >95:5)
(entries 1 and 2). Unfortunately, however, the diastereoselectivity in these
cases was poor (trans/cis = 1:1). This reaction can be applied to the
construction of spirocyclic frameworks bearing the boryl group, which
would otherwise be difficult to synthesize through a one‐step procedure.
Spiro[3.4]octan‐2‐ylmethylboronate (5e) and
spiro[3.5]nonan‐2‐methylboronate (5f) in particular were successfully
obtained in high yields as singularly borylated products (90% and 92%,
respectively) (entries 3 and 4). The application of a substrate containing a
Boc‐protected piperidine moiety (4g) gave the desired nitrogen‐containing
spirocyclic boronate (5g) in good yield (90%) with excellent chemoselectivity
(5g/6g >95:5) (entry 5). Tri‐substituted cyclobutanes (5h and 5i) were formed
in high yields (90% and 83%, respectively) from the corresponding alkenyl
bromides (entries 6 and 7). The reactions of substrates containing aromatic
rings (4j and 4k) afforded the di‐substituted cyclobutylmethyl boronates (5j
and 5k) in excellent yields (entries 8 and 9). Pleasingly, the reaction of a
dienyl halide (4l) proceeded smoothly to produce the desired bis‐boryl
products (5l) bearing spiro[3.3]framework via double borylative cyclization
(entry 10). The five‐membered ring products (5m and 5n) were also
successfully synthesized with a high degree of chemoselectivity (>95:5)
(entries 11 and 12). A silicon‐containing product 5o was obtained in good
yield (entry 13) with a minor amount of the endo‐cyclization product (7%).
Notably, with the exception of entry 13, the endo‐cyclization products
originating from the regioisomeric insertion were not detected in the
reactions shown in Table 3. Unfortunately, this reaction could not be
successfully applied to the formation of six‐membered rings (entry 14).
53
Table 3. Copper(I)‐Catalyzed Borylative exo‐Cyclization of Unactivated
Alkenyl Halidesa
entry substrate producttime (h)
yieldb
(%)
>95:5 94 (1:1)1
5/6selectivity
Ph
Br
(pin)BPh
4c 5c
1.5
>95:5 92 (1:1)2 OBn
Br
(pin)B OBn
4d 5d
1
>95:5 903
4e 5e
4
Br
(pin)B
>95:5 924
4f 5f
4
Br
(pin)B
>95:5 905
4g 5g
4
Br
(pin)BN
N
Boc
Boc
>95:5 906
4h 5h
3
Br
(pin)B
>95:5 837
4i 5i
4
Br
(pin)BMe
Me Me
Me
>95:5 91 (1.3:1)8
4j 5j
4
Br
(pin)B
>95:5 95 (1.4:1)9
4k 5k
4
Br
(pin)B
54
As shown in Scheme 3, reaction of an alkenyl bromide 4q with an internal
double bond afforded the simple boryl substitution product 6q in 84% yield
exclusively. The cyclization product could not be detected.14
Scheme 3. Copper(I)‐Catalyzed Borylation of Alkenyl Bromide 4q
>95:5 8810c
4l 5l
4
Br
Br B(pin)
(pin)B
>95:5 8611
4m 5m
24
Br
(pin)B
>95:5 87 (1.1:1)12
4n 5n
6(pin)B
Br
>95:5 7413d
4o 5o
4Si (pin)B Si
BrMe
MeMe
Me
>95:5 414e
4p
20Br
(pin)B
5p
aConditions: 4 (0.5 mmol), CuX (0.025 mmol), ligand (0.025 mmol), K(O-t-Bu)/THF (0.6 M,1.0 mL), 2 (0.6 mmol), 30 C . bIsolated yield. Values in parenthese are the stereoselectivity determined by GC analysis. cConditions: 4l (0.5 mmol), CuCl (0.1 mmol), Xantphos (0.1mmol), K(O- t-Bu)/THF (0.73 M, 1.5 mL), 2 (1.1 mmol), 30 C. dThe endo-cyclizationproduct (7%) was detected. eThe reaction resulted in a complex mixture.
Br
CuCl (5 mol %)Xantphos (5 mol %)K(O-t-Bu) (1.2 equiv)
2 (1.2 equiv)THF, 30 C, 12 h
B(pin)
4q 6q, 84%
55
The borylative cyclization products are a useful synthetic block for
preparation of carbocyclic compounds. The cyclization product 5f was
subjected to NaBO3 oxidation, homologation with a halomethyl lithium
reagent, or amination with benzyl azide (Scheme 4).15–17 These reaction
afforded the corresponding alcohol 7f (88%, isolated yield), alkyl boronate 8f
(90%), and benzyl amine 9f (60%), respectively.
Scheme 4. Derivatization of Borylative Cyclization Products
Suzuki‐Miyaura cross‐coupling reaction of borylative cyclization products
(5b and 5g) with aryl halides (9a and 9b) also proceeded in the presence of
Pd/Ruphos catalyst system to produce arylated products in reasonable yields
(11b and 11g, 73% and 65% respectively) (Scheme 5).9a,18
(pin)B
ClCH2Br (2.0 equiv)n-BuLi (1.5 equiv)
THF, 78 C then rt, 4 h
H2C
(pin)B
NaBO3/4H2O (10 equiv)
THF/H2O, rt, 1.5 h
BCl3 (5.0 equiv), rt, 4 hthen BnN3 (3.0 equiv), 0 C , 16 h
CH2Cl2
HO
BnHN
7f, 88%
8f, 90%
9f, 60%
5f
56
Scheme 5. Suzuki‐Miyaura Cross‐Coupling Reaction of Borylative
Cyclization Products 5b and 5g
To further demonstrate the synthetic utility of this reaction, the author
synthesized a biologically active compound, a histamine H3 receptor ligand
12 (IC50: 6.56 nM), containing a piperidine sulfonamide structure (Scheme
6).19 The author first checked the tolerance of sulfonamide functionality in
this reaction; sulfonamides 4r and 4s gave the desired spirocyclic boronates
(5r and 5s) in good yields with excellent chemoselectivity
(cyclization/substitution, >95:5). The boronate ester group in the borylative
cyclization product 5r was functionalized through NaBO3 oxidation and
Jones oxidation to afford carboxylic acid 13, which was then coupled with
1‐cyclobutylpiperazine to afford the histamine H3 receptor ligand 12.
iPrO
OiPrCy2P Ruphos
5b +
[Pd2(dba)3] (2 mol %)Ruphos (4 mol %)
toluene/H2O (10:1), 80 Ct-BuONa (3.0 equiv), 48 h
F
Br
F
10a 11b, 73%
+
Br
CF3
[Pd2(dba)3] (2 mol %)Ruphos (4 mol %)
toluene/H2O (10:1), 80 Ct-BuONa (3.0 equiv), 48 h
CF3N
Boc
11g, 65%
5g
10b
57
Scheme 6. Synthesis of Spirocyclobutyl Piperidine Structure through
Borylative Cyclization: Application to the Sysnthesis of Histamine H3
Receptor Ligand 12
Liu, Steel, and Marder et al. reported the cyclization of 4m to 5m in their
mechanistic studies of the boryl substitution reactions with a copper(I)/PPh3
catalyst system (Scheme 7).9a,10 The cyclization was suggested the possibility
of a radical‐process, in which the borylcopper(I) species initially attacked the
CBr bond and then underwent a radical‐mediated cyclization. However, the
radical scavenger experiment did not support this idea. The
copper(I)/Xantphos catalyst system also gave the same product (Table 3,
entry 11), although the reaction should proceed via the addition of
borylcopper(I) to the alkene followed by an intermolecular substitution.
5 mol % CuCl / Xantphos(pin)B-B(pin) (1.2 equiv)
t-BuOK (1.2 equiv)THF, 30 C, 4 h
B(pin)
NR
NR
Br
R = PhSO2, 4rR = p-TolSO2, 4s
R = PhSO2, 5r, 82% (5r/6r = >95:5)R = p-TolSO2, 5s, 80% (5r/6r = >95:5)
1. NaBO3/4H2O THF/H2O, rt, 1 h
2. Jones Reagent acetone, 0 C, 1 h
5r
O
NR
HO
1364% (2 steps)
NHN
HBTU, iPrNEtDMF, rt, 2 h
O
NS
O O
N
N
12, 91%
Histamine ReceptorLigand
58
Scheme 7. Borylation of 4m in the presence of Copper(I)/PPh3 Catalysis
The difference in the mechanisms between the two processes was
evidenced by the protonation experiments (Scheme 8). When Xantphos was
used as the ligand, the protonated compounds (6m and 6m’) were isolated as
the major products. In contrast, the reaction with PPh3 predominantly gave
the cyclization product (5m) even in the presence of MeOH. The author
supposes that the reaction with PPh3 proceeds through a radical‐related
mechanism. The product switch for 4a and 4b (Table 2 and Scheme 2) also
corresponds well with the difference highlighted for the above mechanisms.
The alkylcopper(I) mediated substitution can afford cyclization of three‐ and
four‐membered rings; however, radical‐mediated cyclization of both three‐
and four‐membered rings is highly unfavorable.20
Br
OB
OB
O
O
(1.5 equiv)
+
CuI (10 mol %)PPh3 (13 mol %)
LiOMe (2.0 equiv)DMF, rt, 18 h
(pin)B+
5m, 52%
B(pin)4m
6mnot detected
2.3 x 105 s-1
Radical Cyclization
59
Scheme 8. Borylation Reactions of 4m in the Presence of Proton Source
The borylative exo‐cyclization of chiral substrates was also investigated to
observe the stereochemistry of the leaving group (Scheme 9). Optically active
(S)‐4d was subjected to the B2(pin)2/CuCl/K(O‐t‐Bu)/Xantphos borylation
system. The reaction proceeded in a perfect stereoselective manner in terms
of the substitution at the C2 position, in that the alkyl halide substitution
showed inversion of stereochemistry, whereas no selectivity was observed
around the C1 position, reflecting the lack of stereoselectivity during the
initial borylcopper(I) addition to the double bond. This high level of
stereoselectivity also excluded the possibility of a radical‐related mechanism
during the cyclization step.
Scheme 9. Borylative Cyclization of Optically Active Substrate
CuCl / ligand (5 mol %)K(O-t-Bu) (1.2 equiv)
MeOH (2.0 equiv), THF(pin)B-B(pin) (1.2 equiv)30 C, 5 h
Br
(pin)B
H Br
H
B(pin)+ (pin)B+
71% (L = Xantphos)
5% (L = PPh3)4% (L = Xantphos)
5% (L = PPh3)15% (L = Xantphos)
21% (L = PPh3)
4m
6m 6m' 5m
C
OBn
H Br
(S)-4d
>99% ee
5 mol % CuCl / Xantphos(pin)B-B(pin) (1.2 equiv)
t-BuOK (1.2 equiv)THF, 30 C, 1 h88% (trans/cis = 1:1)
COBn
BO
O
COBn
H
H
BO
O
(1S,2S)-trans-5d
99% ee
(1R,2S)-cis-5d
99% ee
12
+
60
Preliminary density functional theory (DFT) calculations
(B3PW91/cc‐pVDZ) were used to explain the strong ligand influence
observed in this reaction. The activation free energy for the addition of a
model borylcopper(I)/Xantphos intermediate (I) to ethylene (II) was lower
than those with the PPh3 and NHC (IMes) complexes by 1.43 and 1.35
kcal/mol (Table 4). The HOMO level of I with Xantphos (4.49 eV) was
considerably higher than those of the PPh3 (5.20 eV) and NHC (4.71 eV)
complexes, indicating that the Xantphos complex had a stronger back
donation ability to alkenes, which is considered to be important for the
addition of borylcopper(I) to alkenes.12 To understand the ligand effect,
distortion/interaction analysis was also performed.21 When the structures of
the borylcopper(I) complexes (I) with PPh3 and NHC were distorted to the
structure in the transition states, the additional free energies were needed by
16.2 and 18.6 kcal/mol, respectively (Supporting Information). Contrary, the
Xantphos complex only required 11.7 kcal/mol for the conformation change
from I to TS, indicating the pre‐activation nature of the Xantphos complex (I)
in the addition to alkenes.
Table 4. DFT Calculations (B3PW91/cc‐pVDZ) of Alkene Addition Step in
Copper(I)‐Catalyzd Borylation
B CuLO
OI
C CH
H H
Me
+
II
BCu
C CH
H H
MeIII
O
OL
C CH
H HMe
TS
CuL
BO
O
C C
H
HMe
H
P
CuLBO
O
L
Xantphos
PPh3
IMes
G (298K, 1.0 atm, gas-phase)a / kcal mol-1
I+II III TS P
0
0
0
7.1 (6.5)
3.5 (10.4)
7.3 (8.1)
17.6 (2.1)
19.0 (3.6)
18.9 (3.0)
11.4 (24.9)
16.2 (30.5)
14.2 (30.1)aElectronic energies are shown in parentheses.
61
DFT calculations revealed that the activation barrier difference is a key
factor for this regioselectivity (Scheme 10). In the proposed alkylcopper
intermediate, the less bulky Cu(xantphos) moiety is placed at the sterically
congested internal carbon. Based on the structure of the addition product,
this seems to be unfavorable. DFT calculations with propene substrate for the
two diastereomeric pathways were conducted. Path A can afford the major
product for the addition of borylcopper(I), whereas path B corresponds to the
formation of the minor product. The activation free energy for path A was
lower than that of path B by 1.94 kcal/mol. Contrary, ‐complex IIIP and the
alkylcopper product PP were more stabilized in path B than in path A. In the
transition state, the C1 carbon, which will bind to boron atom in the product,
formed a transient five‐coordinated geometry with highly congested
environment. The substituent on the C1 atom thus causes destabilization of
the transition state. This can explain the transition state in path A has the
lower barrier as compared to those in path B.
62
Scheme 10. DFT Calculations (B3PW91/cc‐pVDZ) for Two Diastereomeric
Pathways
A proposesd reaction mechanism for the process is shown in Scheme 11.
The copper(I) alkoxide (A) formed via the reaction of the CuCl, ligand, and
K(O‐t‐Bu) mixture initially reacts with diboron to form the borylcopper(I)
intermediate (B). When Xantphos was used as the ligand, the borylcopper(I)
intermediate possessed the ability to add to the CC double bond of the
substrate 4 (path a) to form the alkylcopper(I) species with concomitant
formation of an ate complex (C) by coordination of the alkoxide. Subsequent
sequential oxidative addition and elimination of bromide with inversion of
the stereochemistry gives the cyclic copper(III) intermediate (D), in a manner
similar to that of the SN2 reaction postulated for the alkyl substitution of alkyl
halides with cuprates.22 Subsequent reductive elimination of the copper
moiety from the D produces the cyclization product 5, as well as reproducing
A. The cyclization of six membered rings would not proceed according to
B CuLO
O
+
C CCH3
HH
H
C CCH3
HH
H
BCu
O
O L
C C CH3HH
H
B Cu
O
O
L
C C
B
CH3
OO
HH
CuLH
C CH
HH
H3C
BCu
O
O L
C C HHH
H3C
B Cu
O
O
L
C C
B
H
OO
H3CH
CuLH
I
0 (0)
path A
path B
IIIPA
IIP
+10.7 (3.7) TSPA +22.0 (5.8) PPA 6.5 (21.5)
IIIPB +8.9 (5.4) TSPB +24.0 (7.0) PPB 7.9 (22.9)
majorproduct
minarproduct
aRelative G value (kcal / mol) at 298 K, 1.0 atm, gas phase. Electronic energies are shown in parentheses.
63
this mechanism because the seven membered ring intermediate (D, n = 4)
appeared to be unstable (Table 3, entry 14). When a monophosphine were
used as the ligand, the reactivity of the borylcopper(I) towards alkene
addition would be less favourable (path b), with boryl substitution (n = 1,2)
or radical cyclization proceeding (n = 3) instead.
Scheme 11. Possible Reaction Pathway
Conclusion
In summary, the auther have identified an unprecedented reactivity of
borylcopper(I) toward unactivated terminal alkenes and developed a
borylative exo‐cyclization reaction, which allows for the one‐step
construction of alkylboronates with complex structures, such as spirocyclic
frameworks, from simple starting materials. The undesired boryl substitution
of the alkyl bromide moiety in the starting materials was suppressed by
choosing an appropriate ligand (Xantphos), which enhanced the reactivity of
LCu(O-t-Bu)
B CuL
Br
B
LCuBr+
n
substitution insertion
+ K(O-t-Bu)– KBr
n
L = Xantphos+ K(O-t-Bu)
oxidativeaddition
n
Cu
B
Lt-BuO III
reductiveelimination
nB
CuCl
+ K(O-t-Bu) – KCl
B B+BOR–– KBr
Brn
Cu
B
Lt-BuO I–
K+
A
B
C
D
5
6, n = 1, 2
L = PPh3
B
or
5, n = 3
64
the key borylcopper(I) intermediate towards addition to the carbon‐carbon
double bonds.
65
Experimental
General.
Materials were obtained from commercial suppliers and purified by
standard procedures unless otherwise noted. Solvents were also purchased
from commercial suppliers, degassed via three freeze‐pump‐thaw cycles, and
further dried over molecular sieves (MS 4A). NMR spectra were recorded on
JEOL JNM‐ECX400P spectrometer (1H: 400 MHz and 13C: 100 MHz).
Tetramethylsilane (1H) and CDCl3 (31C) were employed as external standards,
respectively. CuCl (ReagentPlus® grade, 224332‐25G, ≥99%) and K(O‐t‐Bu) /
THF (1.0 M, 328650‐50ML) were purchased from Sigma‐Aldrich Co. and
used as received. 1,4‐Diisopropylbenzene was used as an internal standard to
determine GC yield. GLC analyses were conducted with a Shimadzu
GC‐2014 or GC‐2025 equipped with ULBON HR‐1 glass capillary column
(Shinwa Chemical Industries) and a FID detector. HPLC analyses with chiral
stationary phase were carried out using a Hitachi LaChrome Elite HPLC
system with a L‐2400 UV detector. Recycle preparative gel permeation
chromatography was conducted with a JAI LC‐9101 using CHCl3 as the
eluent. Elemental analyses and high‐resolution mass spectra were recorded
at the Center for Instrumental Analysis, Hokkaido University.
A Representative Procedure for the Copper(I)‐Catalyzed Hydroboration
of 1a (Table 1):
Copper chloride (2.5 mg, 0.025 mmol) and bis(pinacolato)diboron (152.4
mg, 0.6 mmol), Xantphos (14.5 mg, 0.025 mmol) were placed in an oven‐dried
reaction vial. After the vial was sealed with a screw cap containing a
teflon‐coated rubber septum, the vial was connected to a vacuum/nitrogen
manifold through a needle. It was evacuated and then backfilled with
nitrogen. This cycle was repeated three times. THF (0.4 mL) and
K(O‐t‐Bu)/THF (1.0 M, 0.6 mL, 0.6 mmol) were added in the vial through the
rubber septum. After 1‐hexene (1a, 42 mg, 0.5 mmol) was added to the
66
mixture at 30 °C, MeOH (415 μL, 1.0 mmol) was added dropwise. After the
reaction was complete, the reaction mixture was passed through a short silica
gel column eluting with Et2O/hexane (20:80). The crude mixture was further
purified by flash column chromatography (SiO2, Et2O/hexane, 0:100–4:96) to
give the corresponding alkylboronate 3a as a colorless oil. The flash column
chromatography should be done within 5 min after the crude mixture was
applied on the silica gel surface; otherwise the products are obtained in low
yield.
A Representative Procedure for the Copper(I)‐Catalyzed Borylative
Cyclization of Alkenyl Halides 4.
Copper chloride (2.5 mg, 0.025 mmol) and bis(pinacolato)diboron (152.4
mg, 0.6 mmol), Xantphos (14.5 mg, 0.025 mmol) were placed in an oven‐dried
reaction vial. The vial was sealed with a screw cap containing a teflon‐coated
rubber septum. The vial was connected to a vacuum/nitrogen manifold
through a needle, evacuated and backfilled with nitrogen. THF (0.4 mL) and
K(O‐t‐Bu)/THF (1.0 M, 0.6 mL, 0.6 mmol) were added in the vial through the
rubber septum. Then alkenyl halide 4 (0.5 mmol) was added dropwise at
30 °C. After the reaction was complete, the reaction mixture was passed
through a short silica gel column eluting with Et2O/hexane (20:80). The crude
mixture was further purified by flash column chromathography (SiO2,
Et2O/hexane, 0:100–4:96) to give the corresponding cyclization product 5.
Starting Materials.
The starting materials (1a, 4a, 4b, 4m, and 4p) were purchased from
commercial suppliers. (E)‐1‐Bromohex‐3‐ene (4p) was prepared by
bromination of (E)‐hex‐3‐en‐1‐ol with CBr4/PPh3 reagents.23 The starting
materials were dried over MS4A before use, without further purification.
Preparation of (3‐bromohex‐5‐en‐1‐yl)benzene (4c).
67
In a vacuum dried 100 mL round bottomed flask, 3‐phenylpropanal (1.3
mL, 10 mmol) was dissolved in dry Et2O (10 mL) and was cooled to 0 °C
under nitrogen atmosphere. A Et2O solution of allyl magnesium bromide (1.3
M, 11.5 mL, 15 mmol) was then added dropwise for 10 min. After stirred for
3 h, the reaction mixture was quenched by addition of saturated NH4Cl aq.
and extracted with Et2O three times. The combined organic layer was then
dried over MgSO4. After filtration, the solvents were removed by
evaporation. The crude product was purified by flash column
chromatography to obtain the corresponding homoallylic alcohol (1.058 g, 6.0
mmol, 60%) as a colorless oil.
In a 50 mL round bottomed flask, CBr4 (1.094 g, 3.3 mmol) and the
homoallylic alcohol (529 mg, 3.0 mmol) were dissolved in dry THF (12 mL)
and mixture was cooled to 0 °C. PPh3 (866 mg, 3.3 mmol) was then added
portion wise and the reaction mixture was stirred for 20 min. The reaction
mixture was quenched by addition of water and extracted three times with
Et2O. The combined organic layer was dried over MgSO4. After filtration, the
solvents were removed by evaporation. The hexane suspension of the crude
mixture was filtered and concentrated by evaporation. The crude product
was purified by silica gel chromatography and bulb‐to‐bulb distillation (20
Pa, 90 °C) to obtain 4c (395 mg, 1.65 mmol, 55%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 2.08–2.13 (m, 2H), 2.64 (t, J = 6.8 Hz, 2H),
2.75 (dt, J = 8.2, 13.9 Hz, 1H), 2.91 (dt, J = 7.0, 13.9 Hz, 1H), 3.99 (quin, J = 6.7
Hz, 1H), 5.10–5.14 (m, 2H), 5.78–5.88 (m, 1H), 7.19–7.31 (m, 5H). 13C NMR
(100 MHz, CDCl3, δ): 33.6 (CH2), 39.9 (CH2), 43.3 (CH2), 55.3 (CH), 117.9 (CH2),
126.0 (CH), 128.4 (CH), 128.5 (CH), 134.6 (CH), 140.8 (C). HRMS–EI (m/z): [M–
Br]+ calcd for C12H15, 159.11737; found, 159.11655. Anal. Calcd for C12H15Br: C,
60.27; H, 6.32. Found: C, 60.16; H, 6.37.
OHCPh
MgBr
Et2O, 0 Crt
PhHO
THF, 0 Crt
CBr4, PPh3 PhBr
4c
68
Preparation of {[(2‐bromopent‐4‐en‐1‐yl)oxy]methyl} benzene (4d).
Anhydrous copper(I) iodide (285.7 mg, 1.5 mmol) was placed into a 100
mL round‐bottomed flask equipped with a mechanical stirrer and a
low‐temperature thermometer. Then 4 mL of THF were added and the flask
was cooled to –20 °C. Vinylmagnesium bromide (1.0 M in THF, 30 mL, 30
mmol) was added dropwise. After stirring for 20 min at –20 °C, benzyl
glycidyl ether (2.3 mL, 15 mmol) in 2 mL of THF was added dropwise. After
stirring for 12 h at –20 °C, the reaction mixture was quenched by addition of
saturated NH4Cl aq. and extracted with Et2O three times. The combined
organic layer was dried over Na2SO4. After filtration, the solvents were
removed by evaporation. The crude product was purified by flash column
chromatography to obtain the homoallylic alcohol (2.556 g, 13.3 mmol, 89%)
as a colorless oil. 4d was then synthesized by bromination with CBr4/PPh3
reagents according to the same procedure described above (445 mg, 1.7
mmol, 35%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 2.54–2.62 (m, 1H), 2.74–2.81 (m, 1H), 3.65–
3.75 (m, 2H), 4.09–4.16 (m, 1H), 4.58 (s, 2H), 5.12–5.17 (m, 2H), 5.78–5.88 (m,
1H), 7.28–7.39 (m, 5H). 13C NMR (100 MHz, CDCl3, δ): 37.8 (CH2), 69.6 (CH),
73.3 (CH2), 73.8 (CH2), 117.6 (CH2), 127.66 (CH), 127.71 (CH), 128.4 (CH), 134.2
(CH), 137.9 (C). HRMS–EI (m/z): [M+Na]+ calcd for C12H15BrO, 277.02040;
found, 277.02013. Anal. Calcd for C12H15BrO: C, 56.49; H, 5.93. Found: C,
56.25; H, 5.86.
Preparation of 1‐allyl‐1‐(bromomethyl)cyclopentane (4e).
OOBn
CuIVinylmagnesium Bromide
THF, 20 Crt
OBnHO
THF, 0 Crt
CBr4, PPh3 OBnBr
4d
69
In a vacuum dried 300 mL of a round bottomed flask,
cyclopentanecarboxylic acid (2.17 mL, 20 mmol) and MeOH (971 L, 24
mmol) were dissolved in dry CH2Cl2 (110 mL) and the flask was cooled to
0 °C under nitrogen atmosphere.
1‐Ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC) (4.60 g, 24 mmol)
and N,N‐dimethyl‐4‐aminopyridine (DMAP) (2.44 g, 20 mmol) were then
added portion wise. After stirred for 4 h at room temperature, the reaction
mixture was quenched by addition of saturated NH4Cl aq. and extracted
with CH2Cl2 three times. The combined organic layer was then dried over
MgSO4. After filtration, the solvents were removed by evaporation. The
crude product was purified by flash column chromatography to obtain the
corresponding methyl ester (1.839 g, 14.3 mmol, 72%) as a colorless oil.
To a 0 °C solution of i‐Pr2NH (2.0 mL, 14.5 mmol) in THF (15 mL) was
added a hexane solution of n‐BuLi (1.62 M, 6.8 mL, 11 mmol) dropwise. The
reaction mixture was stirred for 20 min and then cooled to –78 °C. The
methyl ester (1.282 g, 10 mmol) was added dropwise and the reaction
mixture was stirred for 1 h at –78 °C. Allylbromide (1.3 mL, 15 mmol) was
then added dropwise into the mixture. It was warmed to room temperature
and stirred for 1 h. The reaction mixture was quenched by addition of
saturated NH4Cl aq. and extracted with Et2O three times. The combined
organic layer was then dried over MgSO4. After filtration, the solvents were
removed by evaporation. The crude product was purified by flash column
chromatography to obtain the corresponding methyl ester (1.009 g, 6.0 mmol,
60%) as a colorless oil.
HO
OEDCDMAPMeOH
CH2Cl20 Crt
MeO
O 1. (i-Pr)2NH, BuLi2. Allybromide
THF, 78 Crt
OO
1. LiAlH4, 0 C
2. CBr4, PPh3 THF, 0 Crt
Br
4e
70
To a slurry of LiAlH4 (342 mg, 9 mmol) in Et2O (10 mL) was added a
solution of the methyl ester (1.001g, 6 mmol) in Et2O (6 mL) dropwise at 0 °C.
After stirred for 2 h, the reaction mixture was quenched by addition of water
and stirred until a white solid was formed. The mixture was filtered and
dried over MgSO4. The solvents were removed by evaporation under
reduced pressure to obtain the alcohol (789 mg, 5.6 mmol, 94%) with
acceptable purity. 4e was then synthesized by bromination with CBr4/PPh3
reagents according to the same procedure described for 4d (224 mg, 1.1 mmol,
22%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 1.49–1.69 (m, 8H), 2.23 (dt, J = 1.1, 6.7 Hz,
2H), 3.37 (s, 2H), 5.76 (ddt, J = 7.7, 10.2, 17.6 Hz, 2H), 5.70–5.81 (m, 1H). 13C
NMR (100 MHz, CDCl3, δ): 25.0 (CH2), 36.2 (CH2), 42.1 (CH2), 44.1 (CH2), 46.6
(C), 118.0 (CH2), 134.6 (CH). HRMS–EI (m/z): [M–C3H6]+ calcd for C6H9Br,
159.98875; found, 159.98845.
Preparation of 1‐allyl‐1‐(bromomethyl)cyclohexane (4f).
4f was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 1.36–1.48 (m, 10H), 2.16 (d, J = 7.7 Hz, 2H),
3.37 (s, 2H), 5.09–5.16 (m, 2H), 5.75 (ddt, J = 7.7, 10.2, 17.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3, δ): 21.5 (CH2), 26.0 (CH2), 33.9 (CH2), 36.7 (C), 40.1 (CH2),
43.8 (CH2), 118.2 (CH2), 133.5 (CH). HRMS–EI (m/z): [M–C3H5]+ calcd for
C7H12Br, 175.01223; found, 175.01211. Anal. Calcd for C10H17Br: C, 55.31; H,
7.89. Found: C, 55.09; H, 7.87.
Preparation of tert‐butyl 4‐allyl‐4‐(bromomethyl)piperidine
‐1‐carboxylate (4g).
4f
Br
71
4g was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 1.46 (s, 9H), 1.48–1.56 (m, 4H), 2.23 (d, J = 7.8
Hz, 2H), 3.29–3.51 (m, 6H), 5.12–5.19 (m, 2H), 5.66–5.78 (m, 1H). 13C NMR
(100 MHz, CDCl3, δ): 28.4 (CH3), 33.2 (CH2), 35.5 (C), 39.0 (CH2), 41.9 (CH2),
79.5 (C), 119.2 (CH2), 132.4 (CH), 154.8 (C). HRMS–ESI (m/z): [M+Na]+ calcd
for C14H24BrNO2Na, 340.08826; found, 340.08825.
Preparation of 4‐(bromomethyl)‐4‐propylhept‐1‐ene (4h).
4h was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.87–0.93 (m, 6H), 1.18–1.30 (m, 8H), 2.07 (dt,
J = 1.1, 7.7 Hz, 2H), 3.27 (s, 2H), 5.72 (ddt, J = 7.6, 10.2, 17.6 Hz, 2H), 5.67–5.77
(m, 1H). 13C NMR (100 MHz, CDCl3, δ): 14.7 (CH3), 16.3 (CH2), 37.1 (CH2), 39.4
(CH2), 39.5 (C), 42.4 (CH2), 118.1 (CH2), 133.7 (CH). HRMS–EI (m/z): [M–
C3H5]+ calcd for C8H16Br, 191.04353; found, 191.04340.
Preparation of 5‐bromo‐4,4‐dimethylpent‐1‐ene (4i).
4i was prepared from the corresponding methyl ester according to the
procedure described above.
4g
Br
NBoc
4h
Br
4i
Br
MeMe
72
1H NMR (400 MHz, CDCl3, δ): 1.02 (s, 6H), 2.10 (d, J = 7.7 Hz, 2H), 3.28 (s,
2H), 5.07–5.12 (m, 2H), 5.72–5.83 (m, 1H). 13C NMR (100 MHz, CDCl3, δ): 25.6
(CH3), 34.8 (C), 44.1 (CH2), 46.2 (CH2), 118.1 (CH2), 134.1 (CH). HRMS–EI
(m/z): [M]+ calcd for C7H13Br, 176.02006; found, 176.01966.
Preparation of (1‐bromopent‐4‐en‐2‐yl)benzene (4j).
4j was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 2.42–2.50 (m, 1H), 2.61–2.68 (m, 1H), 3.02–
3.09 (m, 1H), 3.56–3.64 (m, 2H), 4.98–5.08 (m, 2H), 5.65 (ddt, J = 7.2, 10.3, 17.5
Hz, 1H), 7.18–7.36 (m, 5H). 13C NMR (100 MHz, CDCl3, δ): 38.0 (CH2), 38.3
(CH2), 47.4 (CH), 117.2 (CH2), 127.0 (CH), 127.6 (CH), 128.4 (CH), 135.3 (CH),
141.7 (C). HRMS–EI (m/z): [M–C3H5]+ calcd for C8H8Br, 182.98093; found,
182.98085. Anal. Calcd for C11H13Br: C, 58.69; H, 5.82. Found: C, 58.42; H, 5.83.
Preparation of 1‐(1‐bromopent‐4‐en‐2‐yl)naphthalene (4k).
4k was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 2.63–2.71 (m, 1H), 2.81–2.89 (m, 1H), 3.68–
3.78 (m, 2H), 3.99 (quin, J = 7.7 Hz, 1H), 4.98–5.14 (m, 2H), 5.69 (ddt, J = 7.1,
10.3, 17.4 Hz, 1H), 7.37 (dd, J = 0.7, 7.3 Hz, 1H), 7.45–7.57 (m, 3H), 7.78 (d, J =
8.4 Hz, 1H), 7.87–7.89 (m, 1H), 8.06 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3, δ): 37.5 (CH2), 37.6 (CH2), 41.0 (CH), 117.4 (CH2), 122.6 (CH), 123.8
(CH), 125.2 (CH), 125.5 (CH), 126.3 (CH), 127.5 (CH), 129.1 (CH), 131.6 (C),
4j
Br
4k
Br
73
134.0 (C), 135.2 (CH), 137.3 (C). HRMS–EI (m/z): [M]+ calcd for C15H15Br,
274.03571; found, 274.03529. Anal. Calcd for C15H15Br: C, 65.47; H, 5.49.
Found: C, 65.47; H, 5.54.
Preparation of 4,4‐bis(bromomethyl)hepta‐1,6‐diene (4l).
The starting material, (2,2‐diallylpropane‐1,3‐diol), was prepared by
LiAlH4 reduction of the diethyl diallylmalonate. To a suspension of NaH
(60wt.%, 400 mg, 10 mmol) in THF (20 mL) was added dropwise the diol
(1.562 g, 10 mmol) at room temperature, TBSCl (1.73 mL, 10 mmol) was then
added and the reaction mixture was stirred for 6 h. The resulting suspension
was diluted with ether and quenched with saturated aqueous Na2CO3. The
mixture was extracted with Et2O three times and dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford the silyl protected product (2.587 g,
9.6 mmol, 96%) as a colorless oil. The monobromo compound was
synthesized by bromination with CBr4/PPh3 reagents. The TBS group was
then removed with TBAF (1.0 M in THF) to obtain the alcohol (701 mg, 3.2
mmol, 32%, 2 step) as a colorless oil. 4l was also prepared by bromination of
the alcohol with CBr4/PPh3 reagents according to the same procedure
described above (279 mg, 1.0 mmol, 50%).
1H NMR (400 MHz, CDCl3, δ): 2.19 (d, J = 7.7 Hz, 4H), 3.38 (s, 4H), 5.18–5.26
(m, 4H), 5.75 (ddt, J = 7.6, 10.0, 17.5 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ):
37.0 (CH2), 39.2 (CH2), 41.1 (C), 119.9 (CH2), 132.0 (CH). HRMS–EI (m/z): [M–
HO
OH
1. NaH2. TBSCl
THF, 0 Crt
TBSO
OH
1. CBr4, PPh3THF, 0 Crt
2. TBAF, THF
HO
Br
THF, 0 Crt
CBr4, PPh3
Br
Br
4l
74
CH2Br]+ calcd for C8H12Br, 187.01223; found, 187.01154. Anal. Calcd for
C9H14Br2: C, 38.33; H, 5.00. Found: C, 38.06; H, 4.89.
Preparation of 1‐(1‐bromohex‐5‐en‐2‐yl)naphthalene (4n).
4n was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 1.92–2.05 (m, 3H), 2.20–2.31 (m, 1H), 3.61–
3.72 (m, 2H), 3.92 (brs, 1H), 4.90–4.97 (m, 2H), 5.72–5.83 (m, 1H), 7.39 (d, J =
7.3 Hz, 1H), 7.46–7.56 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 7.86–7.89 (m, 1H), 8.07
(d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 31.1 (CH2), 32.6 (CH2), 38.5
(CH2), 40.6 (CH), 115.1 (CH2), 122.6 (CH), 123.4 (CH), 125.3 (CH), 125.5 (CH),
126.1 (CH), 127.5 (CH), 129.0 (CH), 131.9 (C), 133.9 (C), 137.8 (CH), 137.8 (C).
HRMS–EI (m/z): [M]+ calcd for C16H17Br, 288.05136; found, 288.05068. Anal.
Calcd for C16H17Br: C, 66.45; H, 5.92. Found: C, 66.26; H, 5.94.
Preparation of (bromomethyl)(but‐3‐en‐1‐yl)dimethylsilane (4o).
In a vacuum dried 100 mL of a round bottomed flask,
(bromomethyl)chlorodimethylsilane (1.364 ml, 10 mmol) was dissolved in
dry Et2O (10 mL) and was cooled to 0 °C under nitrogen atmosphere. A Et2O
solution of homoallyl magnesium bromide (1.3 M, 10 mL, 13 mmol) was then
added dropwise for 10 min. After stirred overnight, the reaction mixture was
quenched by addition of saturated NH4Cl aq. and extracted with Et2O three
times. The combined organic layer was then dried over MgSO4. After
4n
Br
SiMeMe
Br
Cl
MgBr
THF, 0 CrtSiMe
Me
Br
4o
75
filtration, the solvents were removed by evaporation. Because the purity of
the product was not enough even after the flash column chromatography,
the product was then subjected to a recycle gel permeation chromatography
to obtain the pure homoallylsilane 4o (255 mg, 1.2 mmol, 12%) as a colorless
oil.
1H NMR (400 MHz, CDCl3, δ): 0.14 (s, 6H), 0.74–0.80 (m, 2H), 2.07–2.14 (m,
2H), 2.48 (s, 2H), 4.92 (dq, J = 1.6, 10.3 Hz, 1H), 5.02 (dq, J = 1.8, 17.4 Hz, 1H),
5.87 (ddt, J = 6.5, 10.5, 17.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): –4.0 (CH3),
13.2 (CH2), 17.0 (CH2), 27.6 (CH2), 113.2 (CH2), 140.9 (CH). HRMS–EI (m/z):
[M–C4H7]+ calcd for C3H8BrSi, 150.95786; found, 150.95753. Anal. Calcd for
C7H15BrSi: C, 40.58; H, 7.30. Found: C, 40.44; H, 7.17.
Preparation of 4‐allyl‐4‐(bromomethyl)‐1‐(phenylsulfonyl)piperidine
(4r).
4r was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 1.60–1.71 (m, 4H), 2.08 (d, J = 7.7 Hz, 2H),
2.98–3.09 (m, 4H), 3.22 (s, 2H), 5.07–5.14 (m, 2H), 5.64 (ddt, J = 7.6, 10.2, 17.9
Hz, 1H), 7.54–7.58 (m, 2H) 7.61–7.65 (m, 1H) 7.76–7.78 (m, 2H). 13C NMR (100
MHz, CDCl3, δ): 32.5 (CH2), 34.7 (C), 38.9 (CH2), 41.0 (CH2), 41.6 (CH2), 119.3
(CH2), 127.3 (CH), 129.0 (CH), 131.7 (CH), 132.7 (CH), 135.9 (C). HRMS–ESI
(m/z): [M+Na]+ calcd for C15H20BrNO2SNa, 380.02903; found, 380.02911.
Preparation of 4‐allyl‐4‐(bromomethyl)‐1‐tosylpiperidine (4s).
4r
Br
NSO2Ph
76
4g was prepared from the corresponding methyl ester according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 1.60–1.71 (m, 4H), 2.08 (d, J = 7.8 Hz, 2H),
2.45 (s, 4H), 2.94–3.07 (m, 4H), 3.22 (s, 1H), 5.07–5.14 (m, 2H), 5.65 (ddt, J = 7.5,
10.0, 17.3 Hz, 1H), 7.34 (d, J =8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3, δ): 21.5 (CH3), 32.6 (CH2), 34.8 (C), 39.1 (CH2), 41.0 (CH2),
41.7 (CH2), 119.4 (CH2), 127.5 (CH), 129.7 (CH), 131.9 (CH), 132.9 (C), 143.6 (C).
HRMS–EI (m/z): [M+Na]+ calcd for C16H22BrNO2SNa, 394.04523; found,
394.04481.
Preparation of optically active
(S)‐{[(2‐bromopent‐4‐en‐1‐yl)oxy]methyl}benzene [(S)‐4d].
(S)‐4d was prepared from the corresponding (R)‐benzyl glycidyl ether
according to the procedure described above. The enantiomeric purity was
determined by HPLC analysis on a chiral phase of a p‐nitorobenzoate
derivative of the alcohol obtained by Pd/C catalyzed hydrogenation of (S)‐4d
(Daicel CHIRALPAK® OJ‐3, 2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C).
(R)‐4d: tR = 29.29 min, (S)‐4d: tR = 31.28 min. [α]D25.0 –7.70 (deg cm3 g‐1 dm‐1) (c
1.0 in CHCl3).
Characterization of Borylation Products.
4s
Br
NTs
OOBn
CuIVinylmagnesium Bromide
THF, 20 Crt
OBnHO
THF, 0 Crt
CBr4, PPh3 OBnBr
>99% ee(S)-4d
77
2‐(Cyclopropylmethyl)‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (5a).
1H NMR (400 MHz, CDCl3, δ): –0.01–0.03 (m, 2H), 0.40–0.45 (m, 2H), 0.74–
0.78 (m, 3H), 1.23 (s, 12H). 13C NMR (100 MHz, CDCl3, δ): 5.7 (CH2), 5.9 (CH),
16.0 (br, B–CH2), 24.8 (CH3), 82.9 (C). HRMS–EI (m/z): [M–CH3]+ calcd for
C9H16BO2, 167.12433; found, 167.12411.
2‐(Cyclobutylmethyl)‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (5b).
1H NMR (400 MHz, CDCl3, δ): 0.94 (d, J = 7.8 Hz, 2H), 1.23 (s, 12H), 1.54–
1.64 (m, 2H), 1.72–1.85 (m, 2H), 2.04–2.11 (m, 2H), 2.47 (sep, J= 8.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3, δ): 18.3 (CH2), 20.0 (br, B–CH2), 24.8 (CH3), 30.8 (CH2),
32.4 (CH), 82.8 (C). HRMS–EI (m/z): [M–CH3]+ calcd for C10H17BO2, 181.14017;
found, 181.13968.
2‐(Cyclopentylmethyl)‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (5m).
1H NMR (400 MHz, CDCl3, δ): 0.84 (d, J = 7.3 Hz, 2H), 1.01–1.11 (m, 2H),
1.25 (s, 12H), 1.47–1.65 (m, 4H), 1.74–1.82 (m, 2H), 1.89–2.02 (m, 1H). 13C NMR
(100 MHz, CDCl3, δ): 24.8 (CH3), 25.1 (CH2), 35.0 (CH2), 36.1 (CH), 82.8 (C).
The carbon directly attached to the boron atom was not detected, likely due
to quadropolar relaxation. HRMS–EI (m/z): [M–CH3]+ calcd for C10H20BO2,
195.15563; found, 196.15926. Anal. Calcd for C12H23BO2: C, 68.59; H, 11.03.
5a
B
O
O
B
5b
O
O
B
5m
O
O
78
Found: C, 68.63; H, 11.12.
4,4,5,5‐Tetramethyl‐2‐[(2‐phenethylcyclopropyl)methyl)]‐1,3,2‐dioxaborola
ne (5c).
The product (5c) was obtained as a diastereomeric mixture (1:1). The
stereoselectivity was determined by 1H NMR analysis of the alcohol derived
from H2O2/NaOH oxidation of 5c.
1H NMR (400 MHz, CDCl3, δ): –0.29 (q, J = 4.9 Hz, 0.5H), 0.17–0.27 (m, 1H),
0.42–0.57 (m, 1H), 0.61–0.90 (m, 3.5H), 1.26 (s, 12H), 1.40–1.68 (m, 2H), 2.68–
2.73 (m, 2H), 7.14–7.29 (m, 5H). 13C NMR (100 MHz, CDCl3, δ): 9.8 (br, B–CH2),
10.7 (CH), 11.9 (CH2), 13.1 (CH2), 13.8 (CH), 15.4 (CH), 15.7 (br, B–CH2), 19.6
(CH), 24.7 (CH3), 30.8 (CH2), 35.9 (CH2), 36.2 (CH), 36.5 (CH2), 82.8 (C), 82.9
(C), 125.39 (CH), 125.42 (CH), 128.1 (CH), 128.33 (CH), 128.35 (CH), 142.71 (C),
142.73 (C). HRMS–EI (m/z): [M]+ calcd for C18H27BO2, 286.21041; found,
286.21040.
2‐({2‐[(Benzyloxy)methyl]cyclopropyl}methyl)‐4,4,5,5‐tetramethyl‐1,3,2‐diox
aborolane (5d).
The product (5d) was obtained as a diastereomeric mixture (1:1). The
stereoselectivity was determined by GC analysis of the crude reaction
mixture.
1H NMR (400 MHz, CDCl3, δ): –0.1 (q, J = 5.3 Hz, 0.5H), 0.31–0.42 (m, 1H),
0.66–1.13 (m, 4.5H), 1.24 (s, 12H), 3.23–3.52 (m, 2H), 4.49–4.56 (m, 2H), 7.24–
7.37 (m, 5H). 13C NMR (100 MHz, CDCl3, δ): 10.7 (CH), 10.9 (CH), 11.5 (CH2),
12.3 (CH), 15.2 (CH), 19.3 (CH), 24.69 (CH3), 24.73 (CH3), 70.5 (CH2), 72.2
(CH2), 72.6 (CH2), 74.3 (CH2), 83.0 (C), 127.3 (CH), 127.4 (CH), 127.6 (CH),
(pin)BPh
5c
(pin)B OBn
5d
79
127.7 (CH), 128.2 (CH), 138.6 (C), 138.7 (C). HRMS–EI (m/z): [M+Na]+ calcd for
C18H27BO3Na, 325.19510; found, 325.19433. Anal. Calcd for C18H27BO2: C,
71.54; H, 9.00. Found: C, 71.56; H, 9.26.
4,4,5,5‐Tetramethyl‐2‐(spiro[3.4]octan‐2‐ylmethyl)‐1,3,2‐dioxaborolane (5e).
1H NMR (400 MHz, CDCl3, δ): 0.93 (d, J = 7.3 Hz, 2H), 1.23 (s, 12H), 1.46–
1.61 (m, 10H), 1.99 (dt, J = 2.8, 8.8 Hz, 2H), 2.35 (sep, J= 8.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3, δ): 20.0 (br, B–CH2), 23.6 (CH2), 23.9 (CH2), 24.7 (CH3), 25.9
(CH), 39.1 (CH2), 40.5 (CH2), 42.2 (CH2), 42.4 (C), 82.7 (C). HRMS–EI (m/z):
[M–CH3]+ calcd for C15H24BO2, 235.18720; found, 235.18696. Anal. Calcd for
C15H27BO2: C, 72.01; H, 10.88. Found: C, 71.78; H, 11.00.
4,4,5,5‐Tetramethyl‐2‐(spiro[3.5]nonan‐2‐ylmethyl)‐1,3,2‐dioxaborolane (5f).
1H NMR (400 MHz, CDCl3, δ): 0.93 (d, J = 8.1 Hz, 2H), 1.23 (s, 12H), 1.27–
1.45 (m, 12H), 1.93 (dt, J = 2.6, 8.8 Hz, 2H), 2.34 (sep, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3, δ): 20.4 (br, B–CH2), 22.8 (CH2), 23.0 (CH2), 24.7 (CH3), 25.0
(CH), 26.1 (CH2), 35.4 (C), 37.1 (CH2), 41.0 (CH2), 41.2 (CH2), 82.7 (C). HRMS–
EI (m/z): [M]+ calcd for C16H29BO2, 264.22606; found, 264.22586. Anal. Calcd
for C16H29BO2: C, 72.73; H, 11.06. Found: C, 72.46; H, 11.12.
7‐(phenylsulfonyl)‐2‐((4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methyl)‐7
5e
(pin)B
5f
(pin)B
80
azaspiro[3.5]nonane (5g).
1H NMR (400 MHz, CDCl3, δ): 0.96 (d, J = 8.0 Hz, 2H), 1.23 (s, 12H), 1.34–
1.41 (m, 4H), 1.44 (s, 9H), 1.54 (t, J = 5.1 Hz, 2H), 1.98–2.03 (m, 2H), 2.41 (sep, J
= 8.4 Hz, 1H), 2.87 (t, J = 5.7 Hz, 2H), 2.96 (t, J = 5.7 Hz, 2H), 7.50–7.54 (m, 2H)
7.57–7.61 (m, 1H) 7.74–7.76 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): 20.0 (br,
B–CH2), 24.8 (CH3), 25.0 (CH), 28/4 (CH3), 33.7 (C), 36.1 (CH2), 39.7 (CH2), 40.2
(CH2), 79.0 (C), 82.9 (C) 155.0 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C20H36BNO4Na, 388.26296; found, 388.26309.
2‐[(3,3‐Dipropylcyclobutyl)methyl]‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane
(5h).
1H NMR (400 MHz, CDCl3, δ): 0.83–0.93 (m, 8H), 1.06–1.41 (m, 10H), 1.23 (s,
12H), 1.86–1.92 (m, 2H), 2.34 (sep, J = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3,
δ): 14.8 (CH3), 14.9 (CH3), 17.0 (CH2), 17.3 (CH2), 20.3 (br, B–CH2), 24.7 (CH3),
25.0 (CH), 37.2 (C), 39.9 (CH2), 40.8 (CH2), 43.2 (CH2), 82.7 (C). HRMS–EI
(m/z): [M]+ calcd for C17H33BO2, 280.25736; found, 264.25722. Anal. Calcd for
C17H33BO2: C, 72.86; H, 11.87. Found: C, 72.82; H, 11.98.
2‐[(3,3‐Dimethylcyclobutyl)methyl]‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane
5g
(pin)B
NBoc
5h
(pin)B
81
(5i).
1H NMR (400 MHz, CDCl3, δ): 0.92 (d, J = 8.0 Hz, 2H), 1.02 (s, 3H), 1.10 (s,
3H), 1.23 (s, 12H), 1.40 (dt, J = 2.6, 9.3 Hz, 2H), 1.90 (dt, J = 2.7, 9.0 Hz, 2H),
2.37 (sep, J = 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 20.0 (br, B–CH2), 24.5
(CH), 24.8 (CH3), 28.5 (CH3), 31.3 (CH3), 43.4 (CH2), 82.7 (C). HRMS–EI (m/z):
[M–CH3]+ calcd for C12H22BO2, 209.17151; found, 209.17127.
4,4,5,5‐Tetramethyl‐2‐((3‐phenylcyclobutyl)methyl)‐1,3,2‐dioxaborolane
(5j).
The product (5j) was obtained as a diastereomeric mixture (1.3:1). The
stereoselectivity was determined by 1H NMR analysis of the crude reaction
mixture.
1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J = 7.7 Hz, 2H), 1.16 (d, J = 8.1 Hz,
2H), 1.24 (s, 12H), 1.25 (s, 24H), 1.69–1.78 (m, 2H), 2.04–2.10 (m, 2H), 2.31–
2.59 (m, 6H), 3.24–3.34 (m, 1H), 3.62 (quin, J = 8.3 Hz, 1H), 7.13–7.32 (m, 10H).
13C NMR (100 MHz, CDCl3, δ): 19.0 (br, B–CH2), 24.5 (CH3), 24.7 (CH3), 27.4
(CH), 28.0 (CH), 35.9 (CH), 36.35 (CH), 36.41 (CH2), 82.77 (C), 82.80 (C), 125.36
(CH), 125.44 (CH), 126.3 (CH), 128.0 (CH), 128.1 (CH), 146.0 (C), 146.6 (C).
HRMS–EI (m/z): [M–CH3]+ calcd for C16H22BO2, 257.17128; found, 257.17105.
4,4,5,5‐Tetramethyl‐2‐{[3‐(naphthalen‐1‐yl)cyclobutyl]methyl}‐1,3,2‐dioxabo
5i
(pin)BMe
Me
5j(pin)B
82
rolane (5k).
The product (5k) was obtained as a diastereomeric mixture (1.4:1). The
stereoselectivity was determined by GC analysis of the crude reaction
mixture.
1H NMR (400 MHz, CDCl3, δ): 0.99 (d, J = 7.7 Hz, 2H), 1.22–1.27 (m, 2H),
1.23 (s, 12H), 1.25 (s, 12H), 1.84–1.92 (m, 2H), 2.22–2.28 (m, 2H), 2.46–2.65 (m,
5H), 2.71–2.78 (m, 1H), 3.84–3.93 (m, 1H), 4.23 (quint, J = 7.9 Hz, 1H), 7.33 (d, J
= 7.4 Hz, 1H), 7.40–7.51 (m, 8H), 7.67–7.71 (m, 2H), 7.81–7.91 (m, 3H), 7.97–
8.00 (m, 1H). 13C NMR (100 MHz, CDCl3, δ): 19.0 (br, B–CH2), 24.7 (CH3), 27.7
(CH), 28.5 (CH), 33.3 (CH), 34.1 (CH), 35.4 (CH2), 37.7 (CH2), 82.78 (C), 82.82
(C), 121.9 (CH), 122.5 (CH), 124.15 (CH), 124.25 (CH), 125.2 (CH), 125.3 (CH),
125.4 (CH), 126.1 (CH), 126.2 (CH), 128.45 (CH), 128.54 (CH), 131.50 (C),
131.54 (C), 133.6 (C), 133.7 (C), 141.5 (C), 141.6 (C). HRMS–EI (m/z): [M]+ calcd
for C21H27BO2, 322.21041; found, 322.21022.
2,6‐Bis[(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methyl]spiro[3.3]heptan
e (5l).
1H NMR (400 MHz, CDCl3, δ): 0.88 (d, J = 7.7 Hz, 4H), 1.22 (s, 24H), 1.47–
1.60 (m, 4H), 1.97–2.03 (m, 2H), 2.16–2.33 (m, 4H). 13C NMR (100 MHz, CDCl3,
δ): 19.5 (br, B–CH2), 24.7 (CH3), 26.4 (CH), 35.8 (C), 43.3 (CH2), 43.9 (CH2), 82.7
(C). HRMS–EI (m/z): [M+Na]+ calcd for C12H22BO2Na, 399.28539; found,
399.28515.
4,4,5,5‐Tetramethyl‐2‐{[3‐(naphthalen‐1‐yl)cyclopentyl]methyl}‐1,3,2‐dioxab
5k(pin)B
B(pin)
(pin)B 5l
83
orolane (5n).
The product (5n) was obtained as a diastereomeric mixture (1.1:1). The
stereoselectivity was determined by 1H NMR analysis of the crude reaction
mixture.
1H NMR (400 MHz, CDCl3, δ): 0.99–1.02 (m, 4H), 1.18–1.22 (m, 1H), 1.25 (s,
24H), 1.33–1.54 (m, 3H), 1.75–2.14 (m, 6H), 2.19–2.46 (m, 4H), 3.79–3.88 (m,
1H), 3.95 (quin, J = 8.2 Hz, 1H), 7.39–7.52 (m, 8H), 7.67–7.69 (m, 2H), 7.83–7.85
(m, 2H), 8.14 (t, J = 8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ): 18.5 (br, B–
CH2), 24.7 (CH3), 33.1 (CH2), 33.9 (CH), 34.1 (CH2), 35.0 (CH), 35.4 (CH2), 36.1
(CH), 39.7 (CH), 41.1 (CH), 42.0 (CH2), 43.0 (CH2), 82.8 (C), 121.9 (CH), 123.8
(CH), 124.0 (CH), 125.1 (CH), 125.36 (CH), 125.48 (CH), 125.52 (CH), 126.0
(CH), 126.1 (CH), 128.6 (CH), 132.0 (C), 132.1 (C), 133.8 (C), 142.2 (C), 142.7 (C).
HRMS–EI (m/z): [M]+ calcd for C22H29BO2, 336.22606; found, 336.22559.
1,1‐Dimethyl‐3‐[(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methyl]silolan
e (5o).
This compound was obtained as a mixture with endo‐cylization product
(exo/endo 91:9).
1H NMR (400 MHz, CDCl3, δ): 0.08 (s, 6H), 0.42–0.53 (m, 1H), 0.72 (ddd, J =
2.5, 7.1, 14.8 Hz, 1H), 0.81–0.93 (m, 3H), 0.99–1.10 (m, 1H), 1.25 (s, 12H), 1.76–
1.95 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –1.23 (CH3), –1.12 (CH3), 13.2
(CH2), 20.5 (br, B–CH2), 23.0 (CH2), 24.76 (CH3), 24.79 (CH3), 36.2 (CH2), 37.1
(CH), 82.7 (C). HRMS–EI (m/z): [M–CH3]+ calcd for C12H24BO2Si, 239.16386;
found, 238.16649.
(E)‐2‐(hex‐3‐en‐1‐yl)‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane (6q)
5n
(pin)B
5o
(pin)B SiMe
Me
84
1H NMR (400 MHz, CDCl3, δ): 0.86 (t, J = 7.9 Hz, 2H), 0.95 (t, J = 7.7 Hz, 3H),
1.24 (s, 12H), 1.95–2.03 (m, 2H), 2.05–2.17 (m, 2H), 5.44 (dt, J = 2.56, 5.12 Hz,
2H). 13C NMR (100 MHz, CDCl3, δ): 11.0 (br, B–CH2), 14.0 (CH3), 24.9 (CH3),
25.6 (CH2), 26.9 (CH2), 83.0 (C), 130.9 (CH). HRMS–EI (m/z): [M]+ calcd for
C12H23BO2, 210.17934; found, 210.17924.
7‐(phenylsulfonyl)‐2‐((4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methyl)‐7
azaspiro[3.5]nonane (5r).
1H NMR (400 MHz, CDCl3, δ): 0.89 (d, J = 7.7 Hz, 2H), 1.20 (s, 12H), 1.25–
1.30 (m, 2H), 1.55–1.58 (m, 2H), 1.68 (t, J = 5.7 Hz, 2H), 1.85–1.90 (m, 2H), 2.34
(sep, J = 8.5 Hz, 1H), 2.87 (t, J = 2.9, 5.7 Hz, 2H), 2.96 (t, J = 3.0, 5.7 Hz, 2H),
7.50–7.54 (m, 2H), 7.57–7.61 (m, 1H), 7.74–7.76 (m, 2H). 13C NMR (100 MHz,
CDCl3, δ): 21.0 (br, B–CH2), 24.7 (CH3), 24.8 (CH), 32.8 (C), 35.4 (CH2), 38.8
(CH2), 39.9 (CH2), 43.0 (CH2), 43.2 (CH2), 82.8 (C), 127.5 (CH), 128.8 (CH), 132.5
(CH), 136.3 (C). HRMS–ESI (m/z): [M+H]+ calcd for C21H33BNO4S, 406.22179;
found, 406.22174.
2‐[(4,4,5,5‐Tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methyl]‐7‐tosyl‐7‐azaspiro[3.
5]nonane (5s).
1H NMR (400 MHz, CDCl3, δ): 0.89 (d, J = 7.7 Hz, 2H), 1.20 (s, 12H), 1.25–
1.30 (m, 2H), 1.54–1.58 (m, 2H), 1.67 (t, J = 5.7 Hz, 2H), 1.85–1.90 (m, 2H), 2.33
(sep, J = 8.4 Hz, 1H), 2.43 (s, 3H), 2.86 (t, J = 5.5 Hz, 2H), 2.94 (t, J = 5.5 Hz, 2H),
B(pin)
6q
5r
(pin)B
NSO2Ph
5s
(pin)B
NTs
85
7.31 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ):
19.9 (br, B–CH2), 21.3 (CH), 24.6 (CH3), 24.7 (CH3), 32.7 (C), 35.3 (CH2), 38.8
(CH2), 39.8 (CH2), 42.9 (CH2), 43.1 (CH2), 82.6 (C), 127.4 (CH), 129.4 (CH), 133.2
(C), 143.0 (C). HRMS–EI (m/z): [M+Na]+ calcd for C22H34BNO4SNa, 442.21993;
found, 442.21989.
Derivatization of Borylative Cyclization Products.
Experimental Procedure for the NaBO3 Oxidation of 5f.
The oxidation was performed according to the literature procedure.24
In a reaction vial, NaBO3•4H2O (384.7 mg, 2.5 mmol) was dissolved in
THF/H2O (3:2, 5 mL). 5f (66.1 mg, 0.25 mmol) was then added at room
temperature. After stirred for 1.5 h, the reaction mixture was extracted three
times with EtOAc, dried over MgSO4, and filtered. The crude material was
purified by flash column chromatography to obtain the corresponding
alcohol 7f (33.9 mg, 0.22 mmol, 88%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 1.19–1.58 (m, 12H), 1.81–1.86 (m, 2H), 2.40
(sep, J = 8.1 Hz, 1H), 3.58 (d, J = 7.0 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ):
22.6 (CH2), 22.8 (CH2), 26.0 (CH2), 30.5 (CH), 35.1 (CH2), 35.7 (C), 37.7 (CH2),
40.5 (CH2), 68.4 (CH2). HRMS–EI (m/z): [M–OH2]+ calcd for C10H16, 136.12520;
found, 136.12493.
Experimental Procedure for the One Carbon‐Homologation of 5f.
(pin)B
NaBO34H2O(10 equiv)
THF/H2O HO
5f 7f
86
The homologation was performed according to the literature procedure.25
In an oven‐dried reaction vial, 5f (66.2 mg, 0.25 mmol) and
bromochloromethane (64.7 mg, 0.5 mmol) were dissolved in dry THF (2 mL).
After the mixture was cooled to –78 °C, n‐BuLi in hexane (1.64 M, 0.23 mL,
0.38 mmol) was added dropwise. The mixture was stirred at –78 °C for 10
min, and then stirred at room temperature for 4 h. The reaction was
quenched with NH4Cl aq., extracted three times with Et2O, dried over MgSO4,
and filtered. The crude material was then purified by flash column
chromatography to obtain the corresponding homologation product 8f (62.7
mg, 0.225 mmol, 90%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 0.66 (t, J = 8.2 Hz, 2H), 1.22–1.49 (m, 14H),
1.24 (s, 12H), 1.80–1.85 (m, 2H), 2.06 (sep, J = 8.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3, δ): 9.0 (br, B–CH2), 22.8 (CH2), 23.0 (CH2), 24.8 (CH3), 26.1 (CH2), 31.0
(CH2), 32.1 (CH2), 35.2 (C), 37.6 (CH2), 38.5 (CH2), 40.9 (CH2), 82.8 (C). HRMS–
EI (m/z): [M]+ calcd for C17H31BO2, 278.24202; found, 278.24193.
Experimental Procedure for the Amination of 5f.
The amination was performed according to the literature procedure.26
In an oven‐dried reaction vial, CH2Cl2 solution of BCl3 (1.0 M, 1.25 mL, 1.25
mmol) was added under nitrogen atmosphere. 5f (66.1 mg, 0.25 mmol) was
added to the reaction vial with stirring at room temperature. After 4 h, the
volatile materials were removed under reduced pressure, and dry CH2Cl2 (1.5
5f 8f
ClCH2Br (2.0 equiv)n-BuLi (1.5 equiv)
THF, 78 C, rt, 4 h(pin)B(pin)B
(pin)BCH2Cl2
BCl3 (5.0 equiv), rtthen BnN3 (3.0 equiv), 0 C
BnHN
5f 9f
87
mL) was added to the resultant product. The reaction vial was cooled to 0 °C,
and benzyl azide (100 mg, 0.75 mmol) was added to the mixture. After
stirred for 16 h at 0 °C, the reaction mixture was quenched by adding
aqueous NaOH (2.0 M), extracted three times with EtOAc, dried over Na2SO4,
and filtered. The crude material was then purified by flash column
chromatography to obtain the corresponding amine 9f (36.5 mg, 0.15 mmol,
60%) as a yellow oil.
1H NMR (400 MHz, CDCl3, δ): 1.22–1.47 (m, 12H), 1.83–1.89 (m, 2H), 2.37
(sep, J = 8.2 Hz, 1H), 2.64 (d, J = 7.3 Hz, 2H), 3.77 (s, 2H), 7.22–7.35 (m, 5H).
13C NMR (100 MHz, CDCl3, δ): 22.7 (CH2), 22.8 (CH2), 26.0 (CH2), 28.6 (CH),
36.0 (C), 37.1 (CH2), 37.5 (CH2), 40.7 (CH2), 54.0 (CH2), 56.5 (CH2), 126.9 (CH),
128.1 (CH), 128.3 (CH), 140.3 (C). HRMS–ESI (m/z): [M+H]+ calcd for C17H26N,
244.20598; found, 244.20593.
Procedure for the Suzuki‐Miyaura Cross‐Coupling Reaction of 5b
between 4‐Bromo‐2‐fluoro‐1,1’‐biphenyl (10a):
Suzuki‐Miyaura cross‐coupling reaction was performed according to the
literature procedure.27
Pd2(dba)3 (4.6 mg, 0.005 mmol), Na(O‐t‐Bu) (72 mg, 0.75 mmol), Ruphos
(4.7 mg, 0.01 mmol), and 4‐bromo‐2‐fluoro‐1,1’‐biphenyl (62.7 mg, 0.25
mmol) were placed in an oven‐dried reaction vial. After the vial was sealed
with a screw cap containing a teflon‐coated rubber septum, the vial was
connected to a vacuum/nitrogen manifold through a needle. It was evacuated
and then backfilled with nitrogen. This cycle was repeated three times.
Toluene (0.5 mL) and H2O (0.05 mL) and 5b (58.8 mg, 0.30 mmol) were added
in the vial through the rubber septum. The resulting mixture was stirred at
80 °C for 48 h. The reaction mixture was passed through a short silica gel
5b +
[Pd2(dba)3] (2 mol %)Ruphos (4 mol %)
toluene/H2O (10:1), 80 Ct-BuONa (3.0 equiv), 48 h
F
Br
F
10a 11b, 73%
88
column eluting with Et2O. The crude mixture was further purified by flash
column chromatography to give the corresponding coupling product 11b
(43.1 mg, 73%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 1.70–1.79 (m, 2H), 1.82–1.94 (m, 2H), 2.04–
2.12 (m, 2H), 2.59 (sep, J = 7.9 Hz, 1H), 2.72 (d, J = 7.8 Hz, 2H), 6.92–6.99 (m,
2H), 7.24–7.36 (m, 2H), 7.41–7.44 (m, 2H), 7.53–7.55 (m, 2H). 13C NMR (100
MHz, CDCl3, δ): 18.3 (CH2), 28.2 (CH2), 36.9 (CH), 42.4 (CH2), 115.9 (d, J = 22.0
Hz, CH), 124.5 (d, J = 2.8 Hz, CH), 126.2 (d, J = 13.4 Hz, C), 127.3 (CH), 128.4
(CH), 128.9 (d, J = 2.9 Hz, CH), 130.3 (d, J = 3.8 Hz, CH), 135.9 (C), 143.0 (d, J =
6.7 Hz, C), 159.6 (d, J = 248.1 Hz, C). 19F NMR (CDCl3, 372.5 MHz): –118.9.
HRMS–ESI (m/z): [M]+ calcd for C17H17F1, 240.13143; found, 240.13090.
Procedure for the Suzuki‐Miyaura Cross‐Coupling Reaction of 5g
between 1‐Bromo‐4‐(trifluoromethyl)benzene (10b):
Suzuki‐Miyaura cross‐coupling reaction was performed according to the
literature procedure with slight modification.27
Pd2(dba)3 (4.6 mg, 0.005 mmol), Na(O‐t‐Bu) (72 mg, 0.75 mmol), Ruphos
(4.7 mg, 0,01 mmol), and 5g (91.3 mg, 0.25 mmol) were placed in an
oven‐dried reaction vial. After the vial was sealed with a screw cap
containing a teflon‐coated rubber septum, the vial was connected to a
vacuum/nitrogen manifold through a needle. It was evacuated and then
backfilled with nitrogen. This cycle was repeated three times. Toluene (0.5
mL) and H2O (0.05 mL) and bromo‐4‐(trifluoromethyl)benzene (10b) (112.5
mg, 0.5 mmol) were added in the vial through the rubber septum. The
resulting mixture was stirred at 80 °C for 48 h. The reaction mixture was
passed through a short silica gel column eluting with Et2O. The crude
+
Br
CF3
[Pd2(dba)3] (2 mol %)Ruphos (4 mol %)
toluene/H2O (10:1), 80 Ct-BuONa (3.0 equiv), 48 h
CF3N
Boc
11g, 65%
5g
10b
89
mixture was further purified by flash column chromatography to give the
corresponding coupling product 11g (62.3 mg, 65%) as a white solid.
1H NMR (400 MHz, CDCl3, δ): 1.44–1.60 (m, 15H), 1.93–1.98 (m, 2H), 2.52
(sep, J = 8.2 Hz, 1H), 2.77 (d, J = 7.7 Hz, 2H), 3.27 (t, J = 5.3 Hz, 2H) 3.32 (t, J =
5.3 Hz, 2H), 7.22–7.27 (m, 2H), 7.52 (d, J = 7.7 Hz, 2H). 13C NMR (100 MHz,
CDCl3, δ): 28.4 (CH3), 30.0 (CH), 34.0 (C), 36.1 (CH2), 37.8 (CH2), 39.6 (CH2),
40.5 (br, CH2), 43.4 (CH2), 79.2 (C), 125.1 (q, J = 3.5 Hz, CH), 128.7 (CH), 145.0
(C), 154.9 (C). 19F NMR (CDCl3, 372.5 MHz): –62.2. HRMS–ESI (m/z): [M+Na]+
calcd for C21H28O2NF3Na, 406.19643; found, 406.19645.
Preparation of 7‐(phenylsulfonyl)‐7‐azaspiro[3.5]nonane‐2‐carboxylic
acid (13).
In a reaction vial, NaBO3•4H2O (769.3 mg, 5 mmol) and 5r (202.4 mg, 0.5
mmol) was dissolved in THF/H2O (3:2, 5 mL) at room temperature. After
stirred for 1 h, the reaction mixture was extracted three times with Et2O,
dried over MgSO4, and filtered. The crude material was purified by flash
column chromatography to give the corresponding alcohol (128.6 mg) as a
white solid. The obtained alcohol was subjected to the oxidation reaction
using Jones reagent (ca. 2.5 M, 0.25 mL, 0.625 mmol) in acetone at 0 °C. After
1 h, the reaction was quenched by saturated aqueous NH4Cl, extracted three
times with Et2O. The combined organic layer was washed with aqueous
NaOH (0.1 M) and then aqueous layer was acidified with saturated aqueous
NH4Cl, extracted six times with Et2O. The combined organic layer was dried
over MgSO4 followed by evaporation to obtain the corresponding carboxylic
acid 13 (100.1 mg, 64%, 2 steps) as a white solid.
1. NaBO34H2O (10 equiv) THF/H2O, rt, 1 h
2. Jones Reagent acetone, 0 °C, 1 h
N
(pin)B
S
5r
O O
N
HO
S
13O
O O
90
1H NMR (400 MHz, CDCl3, δ): 1.67 (t, J = 5.9 Hz, 2H), 1.71 (t, J = 5.7 Hz, 2H),
1.97 (d, J = 8.8 Hz, 4H), 2.91 (t, J = 5.7 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H), 3.32
(quint, J = 8.9 Hz, 1H), 7.51–7.55 (m, 2H), 7.58–7.62 (m, 1H) 7.74–7.77 (m, 2H).
13C NMR (100 MHz, CDCl3, δ): 31.4 (CH), 33.5 (C), 34.1 (CH2), 35.6 (CH2), 37.2
(CH2), 42.6 (CH2), 42.9 (CH2), 127.4 (CH), 128.9 (CH), 132.7 (CH), 136.0 (C),
181.8 (C). HRMS–ESI (m/z): [M–H]+ calcd for C15H18NO4S, 308.09620; found,
308.09676.
Preparation of (4‐cyclobutylpiperazin‐1‐yl)(7‐(phenylsulfonyl)‐7‐
azaspiro[3.5]nonan‐2‐yl)methanone (12).
The condensation was performed according to the literature procedure.28
In a vacuum dried 20 mL of a round bottomed flask, carboxylic acid (61.8
mg, 0.2 mmol) and N,N‐diisopropylethylamine (DIEA) (41 μL) were
dissolved in DMF (3 mL) under nitrogen atmosphere. A solution of
O‐benzotriazole‐N,N,N’,N’‐tetramethyluronium hexafluorophosphate
(HBTU) (83.4 mg, 0.22 mmol) and 1‐cyclobutylpiperazine (28.1 mg, 0.2
mmol) in DMF (3 mL) was then added dropwise. After stirred for 2 h at room
temperature, the solvent was removed under reduced pressure. The crude
product was then purified by flash column chromatography to obtain the
corresponding condensation product 12 (78.4 mg, 91%) as a white solid. 1H
NMR was in agreement with those in the literature.29 1H NMR (400 MHz,
CDCl3, δ): 1.62–1.76 (m, 6H), 1.80–1.90 (m, 4H), 1.99–2.04 (m, 4H), 2.24 (dt, J =
5.7, 11.7 Hz, 4H), 2.68 (quint, J = 8.0 Hz, 1 H), 2.91 (t, J = 5.3 Hz, 2 H), 2.98 (t, J
= 5.1 Hz, 2 H), 3.10 (quint, J = 8.8 Hz, 1 H), 3.29 (t, J = 4.9 Hz, 2H), 3.59 (t, J =
4.8 Hz, 2H), 7.52–7.56 (m, 2H), 7.59–7.63 (m, 1H), 7.74–7.76 (m, 2H).
O
NR
HO
13
NHN
HBTU, iPrNEtDMF, rt, 2 h
O
NS
O O
N
N
12
91
Determination of Absolute Configuration of trans‐5d and cis‐5d.
The absolute configuration of trans‐5d and cis‐5d were determined by
comparing the optical rotation of the cyclopropylmethyl alcohol obtained by
H2O2 oxidation.7 The ee values were determined by HPLC analysis (Daicel
CHIRALPAK® OJ‐3, 2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C). (S,S)‐7d: tR
= 36.71 min., (R,R)‐7d: tR = 40.92 min, (R,S)‐7d: tR = 23.17 min., (S,R)‐7d: tR =
25.43 min. (S,S)‐7d: [α]D25.1 +10.56 (deg cm3 g‐1 dm‐1) (c 0.9 in CHCl3), (R,S)‐7d:
[α]D23.9 –38.75 (deg cm3 g‐1 dm‐1) (c 0.8 in CHCl3).
Details of DFT calculations
All calculations were performed with the Gaussian 09W (revision C.01)
program package.30 Geometry optimizations were performed with
B3PW91/cc‐pVDZ in the gas‐phase. Xantphos
(4,5‐bis(diphenylphosphino)‐9,9‐dimethylxanthene) ligand was modeled by
4,5‐bis(diphenylphosphino)‐9,9‐xanthene. Molecular orbitals were drawn by
the GaussView 5.0 program. Frequency calculations were conducted on
gas‐phase optimized geometries to check the all the stationary points as
either minima or transition states. Fragment distortion and interaction
energies were calculated with B3PW91/cc‐pVDZ in the gas‐phase.
To understand the ligand effect observed in the borylative exo‐cyclization
reaction, the author conducted distortion/interaction analysis and structure
change analysis of stationary points. Comparison of the calculation results of
ligands indicate that the low activation barrier for the reaction with Xantphos
is due to the preactivation effect on the starting borylcopper(I)/Xantphos
complex as summarized in Figure S1.
Figure S1. Summary of Ligand Effect of Xantphos on the Energy Profile in
Addition of Borylcopper(I) to Alkene
92
Distortion/Interaction Analysis
The distortion/interaction analysis for the transition states in addition
reaction of borylcopper(I) to ethylene indicated the preactivation nature of
the Xantphos ligated borylcopper(I) complex. The energies to deform the
isolated reactants to the transition geometry (Eǂdist) and the energy of
interaction between these deformed reactants are summarized in Table S1.
The ‐complex (III) was omitted because GIII values (complexation) were
positive. The deformation energy for borylcopper(I) complex [Eǂdist (Cu–B)]
with Xantphos ligand (11.7 kcal/mol) is significantly smaller than those of
PPh3 and IMes (16.2 and 18.6 kcal/mol, respectively). The deformation energy
for ethylene [Eǂdist (H2C=CH2)] shows smaller difference. The interaction
energy (Eǂint) of Xantphos complex (–38.8 kcal/mol) is largely smaller than
those of PPh3 and IMes (–44.8 and –49.1 kcal/mol, respectively). This analysis
indicates that a major factor for the low activation barrier of Xantphos
complex at the addition transition state is attributable to the preactivation
nature of borylcopper(I)/Xantphos complex and the resultant early transition
state. In other words, Xantphos ligand make the borylcopper(I) complex
more close to the TS.
Table S2. Distortion/Interaction Analysis for Addtion TS
93
Structure Analysis of Stationary Points for Various Ligands
Comparison of optimization structures of Xantphos (Ix, IIIx, TSx, Px), PPh3 (It,
IIIt, TSt, Pt) and IMes (Ii, IIIi, TSi, Pi) are consistent with the preactivation
nature of Xantphos ligand. Summary of structural parameter and optimized
structures are shown in Table S2 and Figure S2. Among the starting
borylcopper(I) complexes, Ix (L = Xantphos) has the longest Cu–B bond,
indicating the higher degree of activation in Cu–B as compared to It (X =
PPh3) and Ii (X = IMes). The longest Cu–B is also observed in IIIx; on the
contrary, the coordinated carbon‐carbon double bond (C1–C2) is most
weakened in IIIi. TSx has the longest Cu–B bond and the shortest C1–C2
bond length among structures with other ligands. This indicated that, in
Xantphos complexes, the Cu–B bonds are activated throughout the reaction
and that the transition state (TSx) lies early in terms of the bond scission of
C1–C2 bond as compared to the reaction with other ligands.
Table S2. Selected Bond Lengths of Optimized Structures
bond length (Å)
94
ligand Cu–Ba Cu–P C1–C2b
ethylene ‐ ‐ ‐ 1.332
Ix Xantphos 2.038 2.358, 2.357 ‐
It PPh3 2.012 2.238 ‐
Ii IMes 2.011 ‐ ‐
IIIx Xantphos 2.044 2.379, 2.389 1.381
IIIt PPh3 2.029 2.286 1.390
IIIi IMes 2.034 ‐ 1.397
TSx Xantphos 2.094 2.305, 2.300 1.471
TSt PPh3 2.067 2.181 1.490
TSit IMes 2.068 ‐ 1.492
aThe longest Cu–B bond length in the comparative stationary points were
indicated by boldface. bThe shortest C1–C2 bond length in the comparative
stationary points were indicated by boldface.
Figure S2. Optimized Structures (I, III, TS, P) for Xantphos, PPh3 and IMes
with Structural Parameters and Free (in parentheses) and Electronic (in
bracket) Energies
95
96
Structure Analysis of Reaction Pathways in the Reaction of Propene
Coparison of the optimized structures in two different pathways, A and B
gives important information on the regioselectivity (Figure S3). The distance
between C2 and Cu of IIIPA is larger than that of IIIPB. This distortion in IIIPA
would be caused by the steric congestion between C2‐CH3 moiety and the
bulky Xantphos ligand. This could destabilize the IIIPA as compared to IIIPB.
In the transition states, both boron atoms and copper centers are placed at
much closer to the C1 atom as compared to those in the π‐complexes. In
addition, C1 atom took congested five‐coordinated structure containing the
newly forming C1‐B and the breaking C1‐Cu bonds. These structure
alternation make the steric congestion around C1 atom more important than
those of C2 atom in the transition states. Furthermore, C2 atoms take take
more sp3‐like configuration in transition states. This could decrease the steric
interaction between the substituents around C2 atoms and Xantphos ligand.
97
These reversal structural features of the transition state against the
π‐complexe can cause the destabilization in TSPB as compared to TSPA. In the
products (PPA and PPB), interactions between C2 and the bulky Cu moiety
become an important factor again, causing destabilization of PPA. The
difference in electronic properties between ‐CH2 and ‐CHCH3 may influence
the energy profiles in path A and B, although further analysis is required to
clear this.
Figure S3. Two Diastereomeric Pathways for Addition Step of
Borylcopper(I)(Xantphos) Intermediate (I) to Propene (IIp)
98
Figure S4. Optimized Structures for the Transition States (TSX, TSPA, TSPB)
with Structural Parameters and Free (in parentheses) and Electronic (in
bracket) Energies
References and Notes
(1) (a) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, Second Revised Edition; Hall, D. G., Ed.;
Wiley‐VCH: Weinheim, 2011. (b) Boron Compounds, Science of Syntheses;
Kaufmann, D., Ed.; Georg Thieme Verlag: Stuttgart, 2005; Vol. 6. (c)
Chemler, S. R.; Roush, R. W. In Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley‐VCH: Weinheim, 2000, p 403–490.
(2) Examples of palladium‐catalyzed 1,2‐carboboration of alkynes: (a) Daini,
M.; Yamamoto, A.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 2918. (b)
Suginome, M. Chem. Rec. 2010, 10, 348.
(3) Examples of palladium‐catalyzed bolylative cyclization of enynes: (a)
Marco‐Martínez, J.; López‐Carrillo, V.; Buňuel, E.; Simancas, R.;
Cárdenas, D. J. J. Am. Chem. Soc. 2007, 129, 1874. (b) Marco‐Martínez, J.;
Buňuel, E.; López‐Durán, R.; Cárdenas, D. J. Chem.–Eur.J. 2011, 17, 2734.
99
(4) Examples of copper(I)‐catalyzed borylative aldol reactions: (a) Chen, I.
H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
11664. (b) Welle, A.; Petrignet, J.; Tinant, B.; Wouters, J.; Riant, O. Chem.
Eur. J. 2010, 16, 10980. (c) Burns, A. R.; Solana González, J.; Lam, H. W.
Angew. Chem., Int. Ed. 2012, 51, 10827.
(5) For examples of copper(I)‐mediated carboboration of alkynes: (a) Okuno,
Y.; Yamashita, M.; Nozaki, K. Angew. Chem., Int. Ed. 2011, 50, 920. (b)
Zhang, L.; Cheng, J.; Carry, B.; Hou, Z. J. Am. Chem. Soc. 2012, 134, 14314.
(c) Alfaro, R.; Parra, A.; Alemán, J.; Ruano, J. L. G.; Tortosa, M. J. Am.
Chem. Soc. 2012, 134, 15165.
(6) Kehr, G.; Erker, G. Chem. Commun. 2012, 48, 1839.
(7) For copper(I)‐catalyzed endo‐cyclizations: (a) Ito, H.; Kosaka, Y.;
Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47,
7424. (b) Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132,
5990. (c) Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am.
Chem. Soc. 2010, 132, 11440.
(8) For a review including copper(I)‐catalyzed borylation: (a) Dang, L.; Lin,
Z. Y.; Marder, T. B. Chem. Commun. 2009, 3987. (b) Cid, J.; Gulyás, H.;
Carbó, J. J.; Fernández, E. Chem. Soc. Rev. 2012, 41, 3558.
(9) For copper(I)‐catalyzed boryl substitution of alkyl halides: (a) Yang,
C.‐T.; Zhang, Z.‐Q.; Tajuddin, H.; Wu, C.‐C.; Liang, J.; Liu, J.‐H.; Fu, Y.;
Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem., Int. Ed.
2012, 51, 528. Very soon after this publication, a similar reaction was
reported: (b) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. For related
copper(I)‐catalyzed boryl substitution of aryl halides: (c) Kleeberg, C.;
Dang, L.; Lin, Z. Y.; Marder, T. B. Angew. Chem., Int. Ed. 2009, 48, 5350.
(10) One example of copper(I)‐catalyzed reaction that gave the same
cyclization product was reported in ref. 9a. Details are discussed in the
following part of this paper.
(11) Examples of the copper(I)‐catalyzed borylation of activated alkenes: (a)
Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41,
100
6821. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 29,
982. (c) Mun, S.; Lee, J.; Yun, J. Org. Lett. 2006, 8, 4887. (d) Laitar, D.; Tsui,
E.; Sadighi, J. Organometallics 2006, 25, 2405. (e) Lee, Y.; Hoveyda, A. J.
Am. Chem. Soc. 2009, 131, 3160. (f) Sasaki, Y.; Zhong, C. M.; Sawamura,
M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.
(12) (a) Dang, L.; Zhao, H.; Lin, Z.; Marder, T. Organometallics 2007, 26, 2824.
(b) Dang, L.; Lin, Z.; Marder, T. B. Organometallics 2008, 27, 4443. (c)
Sasaki, Y.; Horita, Y.; Zhong, C. M.; Sawamura, M.; Ito, H. Angew. Chem.,
Int. Ed. 2011, 50, 2778.
(13) Diborations of unactivated alkenes were reported. For examples of
transition‐metal catalysis: (a) Ishiyama, T.; Yamamoto, M.; Miyaura, N.
Chem. Commun. 1997, 689. (b) Iverson, C. N.; Smith III, M. R.
Organometallics 1997, 16, 2757. (c) Morgan, J. B.; Miller, S. P.; Morken, J. P.
J. Am. Chem. Soc. 2003, 125, 8702. (d) Ramírez, J.; Corberán, R.; Sanaú, M.;
Peris, E.; Fernández, E. Chem. Commun. 2005, 3056. (e) Ramírez, J.; Sanaú,
M.; Fernández, E. Angew. Chem., Int. Ed. 2008, 47, 5194. For examples of
organocatalysis: (e) Bonet, A.; Pubill‐Ulldemolins, C.; Bo, C.; Gulyás, H.;
Fernández, E. Angew. Chem., Int. Ed. 2011, 50, 7158.
(14) Reaction of a tertiary alkenyl bromide, 1‐allyl‐1‐bromocyclohexane, gave
the corresponding borylative cyclization product in low yield (38%,
determined by 1H NMR).
(15) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem. 1989, 54,
5930.
(16) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(17) Hupe, E.; Marek, I.; Knochel, P. Org. Lett. 2002, 4, 2861.
(18) Dreher, S. D.; Lim, S. E.; Sandrock, D. L.; Molander, G. A. J. Org. Chem.
2009, 74, 3626.
(19) Bernstein, P.; Brown, D.; Griffin, A.; Tremblay, M. C.; Wesolowski, S.
Spirocyclobutyl Piperidine Derivatives. ASTRAZENECA AB US Patent
US 2010/0130477, May 27, 2010.
101
(20) (a) Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem. Soc. 1976, 98, 7024.
(b) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
(21) (a) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc.
2007, 129, 12664. (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem.
Soc. 2008, 130, 10848. (c) Schoenebeck, F.; Houk, K. N. J. Am. Chem. Soc.
2010, 132, 2496.
(22) (a) Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7777. (b) Mori,
S.; Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, 7294. (c)
Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339.
(23)Kozlov, M. V.; Zhu, J.; Philipp, P.; Francke, W.; Zvereva, E. L.; Hansson, B.
S.; Lofstedt, C. Journal of Chemical Ecology 1996, 22, 431.
(24)Kabalka, G.W.; Shoup, T.M.; Goudgaon, N.M. J. Org. Chem. 1989, 54,
5930.
(25)Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(26)Hupe, E.; Marek, I.; Knochel, P. Org. Lett. 2002, 4, 2861.
(27)Yang, C.; Zhang, Z.; Tajuddin, H.; Wu, C.; Liang, J.; Liu, J.; Fu, Y.;
Czyzewska, M.; Steel, P.; Marder, T.; Liu, L. Angew. Chem. Int. Ed. 2012, 51,
528.
(28)Bernstein, P.; Brown, D.; Griffin, A.; Tremblay, M. C.; Wesolowski, S. U. S.
Patent US 2010/0113465 A1, May 27, 2010.
(29)Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.;
Kobayashi, S. Tetrahedron. 1995, 51, 12013.
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Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr.,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
102
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
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Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009.
Chapter 3.
Copper(I)‐Catalyzed Regio‐ and Enantioselective
Monoborylation of Alkenylsilanes
103
Abstract
An asymmetric monoborylation of alkenylsilanes catalyzed by a copper(I)
complex with chiral bisphosphine ligand BenzP* is reported. The reaction
proceeded with excellent regioselectivity and high enantioselectivity to
afford the corresponding optically active organoboronate esters with a
stereogenic C−B bond containing a vicinal silyl group. The synthetic utility of
the product is demonstrated through stepwise transformations to
multifunctional optically active compounds in a stereospecific manner.
Introduction
Enantioenriched chiral organoboron compounds have been recognized as
important chiral building blocks in organic synthesis because they undergo
104
stereospecific transformations of the stereogenic C−B bonds to form C−O,
C−N, or C−C bonds.1 The copper(I)‐catalyzed asymmetric borylation
reactions of C−C double bonds have emerged as a powerful tool to prepare
various optically active organoboronates, which has been researched
extensively recently.2‐7 The key step for the efficient construction of a
stereogenic C−B bond is the regio‐ and enantioselective addition of the
borylcopper(I) species to prochiral alkene substrates.4,6,7
An asymmetric β‐borylation of alkenylsilanes can provide
enantiomerically enriched vicinal borosilanes, which can be derivatized
through stepwise, stereospecific transformations of the boron and silicon
functionalities.3c,8 Ito and Sawamura group previously reported highly
enantioselective copper(I)‐catalyzed intramolecular 1,2‐carboboration of
(Z)‐alkenylsilane derivatives.3c This reaction involved the addition of a chiral
borylcopper(I)/bisphosphine complex to the C−C double bonds in the
substrate to form β‐borylated alkylcopper(I) intermediate A, which is
stabilized by the electronic effect of the silicon group, followed by
stereospecific intramolecular substitution to give the corresponding annular
vicinal borosilane (Scheme 1a).9 The author anticipated that efficient
protonation of the alkylcopper(I) intermediate A’ could also afford optically
active linear vicinal borosilanes (Scheme 1b).10
Scheme 1. Copper(I)‐Catalyzed Asymmetric Borylation Reactions of
(Z)‐Alkenylsilane Substrates
105
At the time that the author initiated this investigation, there were no
reports of such asymmetric borylation; however, Hoveyda and co‐workers
have since reported that chiral N‐heterocyclic carbene copper complexes
catalyze enantioselective β‐borylation of (E)‐alkenylsilanes.11 Although the
reaction proceeded with high regioselectivity, the degree of enantioselection
was moderate in most cases and depended on the structure of the substrates
(68–93% ee).
Scheme 2. Chiral NHC‐Copper(I)‐Catalyzed Asymmetric Borylation of
(E)‐Alkenylsilanes
X Si
B Cu
X Si
Cu(I) cat.QuinoxP*
B B
Previous Work: Annular Vicinal Borosilane Synthesis
This Work: Enantioenriched Liner Vicinal Borosilane Synthesis
MeOH
B
Si
R Si
B H
(Z)
CuOMe
X = -OCO2Me
R Si(Z)
Cu(I) cat.BenzP*
B BR Si
B Cu
CuOMeCO2
up to 97% ee
106
Herein the author reports an efficient catalysis using a copper(I) complex
of the chiral electron‐donating ligand BenzP* to produce optically active
linear vicinal borosilanes with a high degree of enantioselectivity (88–97% ee)
from (Z)‐alkenylsilane substrates. Stepwise transformation of the borylated
products is also demonstrated through the preparation of chiral 1,2‐diol and
1,2‐aminoalcohol derivatives.
Results and Discussion
Following on from previous research, the reaction of (Z)‐1a was first
investigated with CuCl/(R,R)‐QuinoxP* chiral catalyst (5 mol%) in the
presence of bis(pinacolato)diboron 2 (1.5 equiv), K(O‐t‐Bu) base (1.2 equiv)
and MeOH (4.0 equiv) as a proton source in THF at 30 ºC (Table 1).
Pleasingly, the reaction proceeded with good enantioselectivity (92% ee), but
gave only moderate yield (68%) (entry 1). To his disappointment, using the
chiral ligand (R,R)‐segphos, which has previously been found to catalyze
intermolecular 1,2‐carboboration of (Z)‐alkenylsilane derivatives,3c instead of
(R,R)‐QuinoxP* resulted in almost no reaction (entry 2). A series of other
chiral ligands were also screened, including (R,R)‐Me‐Duphos, (S,S)‐BDPP,
N N
Ph Ph
Mes
Et
Et
BF4
PhMe2SiBu
CuCl (5 mol%)chiral imidazolinium salt (5 mol %)Na(O-t-Bu) (80 mol %)
(pin)B-B(pin) (1.1 equiv)MeOH (2.0 equiv), THF, 15 C, 24 h
PhMe2SiBu
B(pin)
84%, 82% ee
107
(R)‐BINAP and the ferrocenyl chiral ligand (R,S)‐Josiphos; they too showed
poor results (entries 3–6).
Then, the author investigated the reaction with (R,R)‐BenzP*,12 which has
a similar structure to QuinoxP*. However, BenzP* is more electron donating
than QuinoxP*, which can facilitate the interaction between the HOMO of the
borylcopper(I) complex and LUMO of the alkenylsilane substrate, enhancing
reactivity while keeping high enatioselectivity.13,14 As a result, the author
successfully improved the yield (91%) and enantioselectivity (95% ee) of the
reaction using chiral ligand (R,R)‐BenzP* (entry 7). A small amount of a
β‐elimination product, 4a (5%) was also detected. Enantiomerically enriched
organoboronates with dimethylphenylsilyl or benzyldimethylsilyl group,
which can be converted into other functional groups more easily than
trimethylsilyl group, were also synthesized with excellent enantioselectivity
(94% ee) through reaction with the copper(I)/(R,R)‐BenzP* catalytic system
(entries 8 and 9, respectively). The reaction of the substrate with a more
sterically hindered diphenylmethylsilyl group also gave a good result (entry
10). Higher enantioselectivity (97% ee) was obtained when the reaction was
conducted at 0 C without β‐elimination side‐product 4a (entry 11).
Various alkenylsilanes were then subjected to the asymmetric
monoborylation in the presence of the copper(I)/(R,R)‐BenzP* catalyst (Table
2). Optically active organoboronates that possess alkyl substituents [R =
CH2CH2Ph (3a), Me (3e), and n‐Bu (3f)] were obtained with high
enantioselectivity (94−97% ee) from the corresponding alkenylsilanes.
Although the reaction of a substrate with a β‐branched alkyl substituent (R
= CH2Cy, 3g) resulted in good enantioselectivity (89% ee), the reaction rate
was relatively slower (58%) because of the considerable steric congestion
around the C–C double bond. Alkenylsilanes with functional groups such as
silyl ether (3h), benzyl ether (3i), and benzoate (3j) were compatible with the
borylation reaction. A substrate containing a chloro group, which is reactive
108
Table 1. Copper(I)‐Catalyzed Enantioselective Monoborylation of
Alkenylsilanes 1 with Bis(pinacolate)diboron 2 under Various Conditionsa
for the copper(I)‐catalyzed boryl substitution, was also applicable (82%, 95%
ee) with no side‐product detected.15 Furthermore, the reaction also proceeded
in the presence of prenyloxy ether (3l), cyano group (3m) and N‐protected
indole (3n) substrates, resulting in good yields with excellent
enantioselectivities (88−96% ee).
entry R3Si Ligand
yield (%)b ee
(%)
1
2
3
4
5
6
7
8
9
10
11
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
PhMe2Si
BnMe2Si
Ph2MeSi
Me3Si
(R,R)-QuinoxP*
(R,R)-Me-Duphos
(S,S)-BDPP
(R)-BINAP
(R)-Segphos
(R,S)-Josiphos
(R,R)-BenzP*
(R,R)-BenzP*
(R,R)-BenzP*
(R,R)-BenzP*
(R,R)-BenzP*
aConditions: 1 (0.5 mmol), CuCl (0.025 mmol), ligand (0.025 mmol), K(O-t-Bu)/THF(0.6 M, 1.0 mL), 2 (0.6 mmol), MeOH (2.0 mmol). bYield was determined by 1H NMRanalysis of the crude mixture. cDetermined by GC or 1H NMR analysis of the crudereaction mixture.
68
64
29
<1
<1
<1
91
94
92
74
81
92
92
74
85
95
94
94
91
97
3 4
<1
<1
<1
<1
<1
<1
5
5
6
9
<1
temp.
(C)
30
30
30
30
30
30
30
30
30
30
0
(R)
N
N P
P
Me
t-Bu
t-Bu
Me
(R,R)-QuinoxP*
P
P
Me
t-Bu
t-Bu
Me
(R,R)-BenzP*
CuCl (5 mol %)ligand (5 mol %)(pin)BB(pin) (2)(1.5 equiv)
K(O-t-Bu) (1.2 equiv)MeOH (4.0 equiv)THF, 30 C, 2 h
(Z)-1a-d(S)-3a-d 4a-d
(pin)B B(pin)
SiR3
PhSiR3
Ph
(pin)BSiR3
B(pin)Ph+
B BO
O O
O=
109
Table 2. Copper(I)‐Catalyzed Enantioselective Monoborylation of Various
Alkenylsilanes
The synthetic utility of the monoborylation products was demonstrated
through selective derivatization. The product 3j was subjected to sequential
NaBO3 and Tamao oxidation to afford the desired enantiomerically enriched
1,2‐diol 5 (64%, 3 steps; 90% ee) in a stereospecific manner for the C−B bond
(Scheme 3).8a,16 The author also conducted the stereospecific amination of 3f
with benzyl azide to give the corresponding amine, followed by oxidation of
5 mol % CuCl5 mol % (R,R)-BenzP*2 (1.5 equiv)
K(O-t-Bu) (1.2 equiv)MeOH (4.0 equiv), THF0 C, 24 h
(Z)-1a-k
SiMe2Ph
O
(pin)B
O
NC
SiMe2Ph
BnO
(pin)B
SiR3
R
(S)-3a, 3e-n
SiR3
R
(pin)B
SiMe3
Ph
(pin)BSiMe2Ph
Me
(pin)BSiMe2Bn
(pin)B
Me
SiMe2Bn(pin)B
SiMe2Bn(pin)B
TBSO
SiMe2Ph(pin)B
Cl
SiMe2Bn(pin)B
SiMe2Ph
O
(pin)B
O
N
Me
SiMe2Ph
O
(pin)B
Me
MeBzO
78%, 97% ee 85%, 94% ee 80%, 94% ee
58%, 89% ee 92%, 97% ee 75%, 89% ee
82%, 95% ee81%, 90% ee 79%, 88% ee
71%, 93% ee 88%, 96% ee
3a 3e 3f
3g 3h 3i
3j 3k 3l
3m 3n
110
the Si−C bond to obtain the optically active 1,2‐aminoalcohol 6 in good yield
with excellent enantiomeric purity (62%, 3 steps; 93% ee).17
Scheme 3. Stepwise Transformation of Monoborylation Products: Synthesis of
1,2‐Diol and 1,2‐Aminoalcohol Derivatives
The E or Z configuration of the substrate strongly influenced the
enantioselectivity of the borylation reaction (Scheme 4). Reaction of (E)‐1a
under standard conditions gave (R)‐3a in lower yield and enantioselectivity
(61%, 89% ee) than those obtained for the same reaction with (Z)‐1 (81%, 97%
ee).11
Scheme 4. Copper(I)‐Catalyzed Enantioselective Monoborylation of (E)‐1a
SiMe2Bn(pin)B
BzO
OAcAcO
BzO
(S)-3j, 90% ee (S)-5, 64% (3 steps) 90% ee
1. NaBO3/4H2O2. TBAF, H2O2 KHCO3, MeOH
3. AcCl, pyridine DMAP, CH2Cl2
1,2-diol
SiMe2Bn(pin)B
Me
(S)-3f94% ee
OHBnHN
Me
(S)-6, 62% (3 steps)93% ee
1. BCl3, CH2Cl22. BnN3, CH2Cl2
3. TBAF, H2O2 KHCO3, MeOH
1,2-aminoalcohol
(E)-1a(R)-3a
SiMe3 SiMe3
Ph
(pin)BPh
5 mol % CuCl5 mol % (R,R)-BenzP*2 (1.5 equiv)
K(O-t-Bu) (1.2 equiv)MeOH (4.0 equiv), THF0 C, 2 h 61%, 89% ee
111
The observed stereochemical outcome of the copper(I)‐catalyzed
monoborylation of (Z)‐ or (E)‐alkenylsilanes can be explained by the
transition states of Cu−B addition across the C−C double bond, as shown in
Figure 1. In the case of the reaction with (Z)‐1, the favored transition state
TS1 is free from steric congestion between the substituents of (Z)‐1 and the
t‐Bu group of the BenzP* chiral ligand, thus producing (S)‐3 as the major
enantiomer. In contrast, the less favored transition state TS2 is destabilized
because one of the t‐Bu groups of the ligand is close to both the silyl groups
and substituents of (Z)‐1. In the case of (E)‐1, one of the t‐Bu groups of the
ligand is involved in steric interactions with either the substituents (TS3) or
silyl groups of (E)‐1 (TS4). Thus, the energy difference between TS3 and TS4
is smaller than that between TS1 and TS2, resulting in higher
enantioselectivity for the substrates with (Z)‐configuration.
Figure 1. Transition State Models for the Enantioselection
TS1 [favored for (Z)-1] TS2 [disfavored for (Z)-1]
TS3 [favored for (E)-1] TS4 [disfavored for (E)-1]
CuP P
C
CB
R
Si
CuP P
C
C
Si
RB
CuP P
C
CRB
Si
CuP P
C
CB
Si
R
112
Preliminary DFT calculations (B3PW91/cc‐pVDZ) were used to explain the
effect of the ligand on reactivity for the borylation of alkenylsilanes (Figure 2).
Marder, Lin and co‐workers reported that the interaction between the
HOMO of the borylcopper(I) intermediate and the LUMO of the electrophile
is crucial for insertion to unsaturated bonds.13 The HOMO levels of the
borylcopper(I) complexes with BenzP* (−4.51 eV) and QuinoxP* (−4.54 eV)
were considerably higher than those containing IMes (4.71 eV) and PPh3
(−5.20 eV).18 This is consistent with the higher reactivity of copper(I)/BenzP*.
Although the hydroboration of alkenylsilane with copper(I)/segphos catalyst
showed poor result, the HOMO level of the segphos complex was higher
than that of BenzP*. This inconsistency would be caused by the steric effect in
the transition state. Further theoretical investigations including the transition
states are required for the full explanation of the reactivity of borylcopper(I)
complexes.
Figure 2. DFT Calculation (B3PW91/cc‐pVDZ) of the HOMO Levels of
Borylcopper(I) Complexes
HO
MO
pot
entia
l ene
rgy
BenzP* (−4.51 eV)
IMes (−4.71 eV)
PPh3 (−5.20 eV)
B3PW91/cc-pVDZ
Segphos (−4.47 eV)
(pin)B−CuLL = (R,R)-BenzP*
QuinoxP* (−4.54 eV)
113
Conclusion
In summary, the auther have developed the copper(I)/BenzP* complex
catalyzed highly regio‐ and enantioselective hydroboration of alkenylsilanes
to afford the synthetically useful optically active liner vicinal borosilanes.
The reaction proceeded with excellent regioselectivity and high
enantioselectivity. The synthetic utility of the protocol was demonstrated by
the stepwise and stereoselective transformation of the products into the
enantioenriched 1,2‐diol and 1,2‐aminoalcohol derivatives.
114
Experimental
General.
Materials were obtained from commercial suppliers and purified by
standard procedures unless otherwise noted. Solvents were also purchased
from commercial suppliers, degassed via three freeze‐pump‐thaw cycles, and
further dried over molecular sieves (MS 4A). NMR spectra were recorded on
JEOL JNM‐ECX400P spectrometer (1H: 400 MHz and 13C: 100 MHz).
Tetramethylsilane (1H) and CDCl3 (31C) were employed as external standards,
respectively. CuCl (ReagentPlus® grade, 224332‐25G, ≥99%) and K(O‐t‐Bu) /
THF (1.0 M, 328650‐50ML) were purchased from Sigma‐Aldrich Co. and
used as received. Mesitylene was used as an internal standard to determine
NMR yield. GLC analyses were conducted with a Shimadzu GC‐2014 or
GC‐2025 equipped with ULBON HR‐1 glass capillary column (Shinwa
Chemical Industries) and a FID detector. HPLC analyses with chiral
stationary phase were carried out using a Hitachi LaChrome Elite HPLC
system with a L‐2400 UV detector. Elemental analyses and high‐resolution
mass spectra were recorded at the Center for Instrumental Analysis,
Hokkaido University. All DFT calculations were performed with the
Gaussian 09W (revision C.01) program package.19 Geometry optimizations
were performed with B3PW91/cc‐pVDZ in the gas‐phase. Molecular orbitals
were drawn by the GaussView 5.0 program. Frequency calculations were
conducted on gas‐phase optimized geometries to check the all the stationary
points as either minima or transition states. Fragment distortion and
interaction energies were calculated with B3PW91/cc‐pVDZ in the gas‐phase.
A Representative Procedure for the Copper(I)‐Catalyzed Asymmetric
Monoborylation of (Z)‐1a (Table 1):
Copper chloride (2.5 mg, 0.025 mmol) and bis(pinacolato)diboron (190.5
mg, 0.75 mmol), (R,R)‐BenzP* (7.1 mg, 0.025 mmol) were placed in an
oven‐dried reaction vial. After the vial was sealed with a screw cap
115
containing a teflon‐coated rubber septum, the vial was connected to a
vacuum/nitrogen manifold through a needle. It was evacuated and then
backfilled with nitrogen. This cycle was repeated three times. THF (0.4 mL)
and K(O‐t‐Bu)/THF (1.0 M, 0.6 mL, 0.6 mmol) were added in the vial through
the rubber septum. After (Z)‐alkenylsilane 1a (102.2 mg, 0.5 mmol) was
added to the mixture at 0 °C, MeOH (80.9 μL, 2.0 mmol) was added
dropwise. After the reaction was complete, the reaction mixture was passed
through a short silica gel column eluting with Et2O/hexane (20:80). The crude
mixture was further purified by flash column chromatography (SiO2,
Et2O/hexane, 0:100–4:96) to give the corresponding hydroboration product 3a
as a colorless oil. The flash column chromatography should be done within 5
min after the crude mixture was applied on the silica gel surface; otherwise
the products are obtained in a low yield.
Preparation of Substrates.
Preparation of (Z)‐trimethyl(4‐phenylbut‐1‐en‐1‐yl)silane (1a).
In a vacuum dried 100 mL round bottomed flask, 4‐phenyl‐1‐butyne (1.92 g,
15.0 mmol) was dissolved in dry THF (15.0 mL) and was cooled to –78 °C
under nitrogen atmosphere. A hexane solution of n‐BuLi (1.62 M, 10.2 mL,
16.5 mmol) was then added dropwise for 10 min. After stirred for 20 min,
chlorotrimethylsilane was added dropwise and the reaction mixture was
stirred at –78 °C for 10 min. Then, it was warmed to room temperature and
stirred for 1 h. The reaction mixture was quenched by addition of saturated
NH4Cl aq. at 0 °C and extracted with Et2O three times. The combined organic
layer was then dried over MgSO4. After filtration, the solvents were removed
SiMe3
Ph
Ph
SiMe3
Ph
1. n-BuLi / Hex2. Me3SiCl
THF, 78 Crt
DIBAL
Z/E = >99:1
Et2O/Hexane (Z)-1a
116
by evaporation. The crude product was purified by flash column
chromatography to obtain the corresponding silylacetylene (2.82 g, 13.9
mmol, 93%) as a colorless oil.
In a 200 mL round bottomed flask, silylacetylene (2.82 g, 13.9 mmol) was
dissolved in dry Et2O (15.0 mL) and mixture was cooled to 0 °C. A hexane
solution of diiobuylaluminium hydride (DIBAL) (1.0 M, 22.5 mL, 22.5 mmol)
was then added portion wise and the reaction mixture was warmed to room
temperature. After stirred for 12 h, the reaction mixture was quenched by
addition of NH4Cl aq. at 0 °C. After filtration, the mixture was extracted
three times with Et2O. The combined organic layer was dried over MgSO4.
After filtration, the solvents were removed by evaporation. The crude
product was purified by silica gel chromatography to obtain (Z)‐1a (Z/E =
>99:1) (2.28 g, 11.2 mmol, 80%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 0.09 (s, 9H), 2.43 (q, J = 7.5 Hz, 2H), 2.68 (t, J
= 8.1, 2H), 5.52 (d, J = 14.3 Hz, 1H), 6.34 (dt, J = 7.3, 14.5 Hz, 1H), 7.17–7.21 (m,
3H), 7.25–7.31 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): 0.18 (CH3), 35.5 (CH2),
36.1 (CH2), 125.9 (CH), 128.3 (CH), 128.4 (CH), 129.7 (CH), 141.7 (C), 147.8
(CH). HRMS–EI (m/z): [M]+ calcd for C13H20Si, 204.13343; found, 204.13325.
Preparation of (Z)‐dimethyl(phenyl)(4‐phenylbut‐1‐en‐1‐yl)silane (1b).
1b was prepared from the corresponding chlorosilane according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.35 (s, 6H), 2.34 (q, J = 7.9 Hz, 2H), 2.58 (t, J
= 7.8 Hz, 2H), 5.68 (d, J = 14.2 Hz, 1H), 6.46 (quint, J = 7.3 Hz, 1H), 7.02 (d, J =
6.8, 2H), 7.13–7.19 (m, 1H), 7.20–7.27 (m, 2H), 7.32–7.38 (m, 3H), 7.50–7.56 (m,
2H). 13C NMR (100 MHz, CDCl3, δ): –0.89 (CH3), 35.7 (CH2), 125.8 (CH), 127.5
(CH), 127.8 (CH), 128.2 (CH), 128.4 (CH), 128.8 (CH), 133.7 (CH), 139.5 (C),
141.6 (C), 149.6 (CH). HRMS–EI (m/z): [M]+ calcd for C18H22Si, 266.14908;
SiMe2Ph
Ph
Z/E = >99:1
1b
117
found, 266.14877.
Preparation of (Z)‐benzyldimethyl(4‐phenylbut‐1‐en‐1‐yl)silane (1c).
1c was prepared from the corresponding chlorosilane according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.065 (s, 3H), 0.067 (s, 3H), 2.12 (s, 2H), 2.36
(q, J = 7.9 Hz, 2H), 2.64 (t, J = 8.1 Hz, 2H), 5.48 (d, J = 14.3 Hz, 1H), 6.37 (dt, J =
7.3, 14.6 Hz, 1H), 6.98 (d, J = 7.7 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1H), 5.10–5.14 (m,
7H). 13C NMR (100 MHz, CDCl3, δ): 1.7 (CH3), 26.6 (CH2), 35.6 (CH2), 35.9
(CH2), 124.0 (CH), 125.9 (CH), 127.6 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH),
128.4 (CH), 140.0 (C), 141.6 (C), 148.9 (CH). HRMS–ESI (m/z): [M+Na]+ calcd
for C19H24NaSi, 303.15395; found, 303.15374.
Preparation of (Z)‐dimethyl(phenyl)(prop‐1‐en‐1‐yl)silane (1d).
1d was prepared from the corresponding chlorosilane according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.62 (s, 3H), 2.28 (q, J = 7.8 Hz, 2H), 2.50 (t, J
= 8.0 Hz, 2H), 5.87 (dd, J = 1.3, 14.1 Hz, 1H), 6.61 (dt, J = 7.41, 14.6 Hz, 1H),
6.86–6.92 (m, 2H), 7.10–7.23 (m, 3H), 7.30–7.41 (m, 6H), 7.50–7.57 (m, 4H). 13C
NMR (100 MHz, CDCl3, δ): –1.9 (CH3), 35.4 (CH2), 36.0 (CH2), 125.6 (CH),
125.7 (CH), 127.9 (CH), 128.2 (CH), 128.4 (CH), 129.1 (CH), 134.6 (CH), 137.4
(C), 141.5 (C), 151.2 (CH). HRMS–EI (m/z): [M]+ calcd for C23H24Si, 328.16473;
found, 328.16396.
SiMe2Bn
Ph
Z/E = >99:1
1c
SiMePh2
Ph
Z/E = >99:1
1d
118
Preparation of (Z)‐benzyl(hex‐1‐en‐1‐yl)dimethylsilane (1f).
1f was prepared from the corresponding terminal alkyne according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.091 (s, 3H), 0.093 (s, 3H), 0.89 (t, J = 7.1 Hz,
3H), 1.25–1.37 (m, 4H), 2.04 (q, J = 7.0 Hz, 2H), 2.16 (s, 2H), 5.43 (dd, J = 0.7,
14.3 Hz, 1H), 6.34 (dt, J = 7.3, 14.5 Hz, 1H), 7.02 (d, J = 7.7 Hz, 2H), 7.06 (t, J =
7.5 Hz, 1H), 7.20 (t, J = 7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ): –1.6 (CH3),
14.0 (CH3), 22.4 (CH2), 26.7 (CH2), 31.8 (CH2), 33.5 (CH2), 123.9 (CH), 126.5
(CH), 128.1 (CH), 128.2 (CH), 140.1 (C), 150.4 (CH). HRMS–EI (m/z): [M]+
calcd for C15H24Si, 232.16473; found, 232.16415.
Preparation of (Z)‐benzyl(3‐cyclohexylprop‐1‐en‐1‐yl)dimethylsilane
(1g).
1g was prepared from the corresponding terminal alkyne according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.08 (s, 6H), 0.88 (q, J = 11.2 Hz, 2H), 1.08–
1.33 (m, 4H), 1.60–1.73 (m, 5H), 1.96 (t, J = 7.1 Hz, 2H), 2.16 (s, 2H), 5.46 (d, J =
14.7 Hz, 1H), 6.36 (dt, J = 7.4, 14.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 2H), 7.06 (t, J =
7.1 Hz, 1H), 7.20 (t, J = 7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ): –1.6 (CH3),
26.4 (CH2), 26.5 (CH2), 26.8 (CH2), 33.2 (CH2), 38.3 (CH), 41.4 (CH2), 123.9 (CH),
127.2 (CH), 128.1 (CH), 128.2 (CH), 140.2 (C), 149.1 (CH). HRMS–EI (m/z):
[M]+ calcd for C18H28Si, 272.19603; found, 272.19541.
Preparation of (Z)‐benzyl(5‐chloropent‐1‐en‐1‐yl)dimethylsilane (1k).
SiMe2Bn
Z/E = >99:1
1f
Me
SiMe2Bn
Z/E = >99:1
1g
119
1k was prepared from the corresponding terminal alkyne according to the
procedure described above.
1H NMR (400 MHz, CDCl3, δ): 0.39 (s, 6H), 1.75 (quint, J = 7.2 Hz, 2H), 2.16
(s, 2H), 2.18 (q, J = 7.6 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), 5.71 (d, J = 14.3, 1H),
6.37 (dt, J = 7.3, 14.5 Hz, 1H), 7.32–7.38 (m, 3H), 7.51–7.57 (m, 2H). 13C NMR
(100 MHz, CDCl3, δ): –1.0 (CH3), 30.8 (CH2), 32.3 (CH2), 44.2 (CH2), 127.7 (CH),
128.4 (CH), 128.8 (CH), 133.6 (CH), 139.3 (C), 148.4 (CH). HRMS–ESI (m/z):
[M–CH3]+ calcd for C12H16ClSi, 223.07098; found, 223.07058.
Preparation of (Z)‐dimethyl(phenyl)(prop‐1‐en‐1‐yl)silane (1e).
In a 200 mL round bottomed flask, chlorodimethylphenylsilane (3.36 mL,
20.0 mmol) was dissolved in dry THF (20.0 mL) and mixture was cooled to
0 °C. A THF solution of propynyl magnesium bromide (0.5 M, 44.0 mL, 22.0
mmol) was then added portion wise and the reaction mixture was stirred for
1 h. The reaction mixture was quenched by addition of NH4Cl aq. and
extracted three times with Et2O. The combined organic layer was dried over
MgSO4. After filtration, the solvents were removed by evaporation. The
crude reaction mixture was purified by silica gel chromatography and to give
the corresponding silylacetylene (2.68 g, 15.4 mmol, 77%) as a colorless oil.
In a 50 mL round bottomed flask, silylacetylene (872 mg, 5.00 mmol) was
dissolved in dry Et2O (5.00 mL) and mixture was cooled to 0 °C. A hexane
solution of DIBAL (1.0 M, 7.50 mL, 7.50 mmol) was then added dropwise and
the reaction mixture was warmed to room temperature. After stirred for 18 h,
the reaction mixture was quenched by addition of NH4Cl aq. at 0 °C. After
SiMe2Ph
Z/E = >99:1
1k
Cl
DIBAL
Et2O/Hexane0 Crt
SiMe2Ph
Me
1eZ/E = >99:1
PhMe2SiCl
THF, 0 CrtMe MgBr Me SiMe2Ph
120
filtration, the mixture was extracted three times with Et2O. The combined
organic layer was dried over MgSO4. After filtration, the solvents were
removed by evaporation. The crude product was purified by silica gel
chromatography to obtain (Z)‐1e (Z/E = >99:1) (714 mg, 4.10 mmol, 81%) as a
colorless oil.
1H NMR (400 MHz, CDCl3, δ): 0.39 (s, 6H), 1.72 (d, J = 7.0 Hz, 3H), 5.66 (dt,
J = 1.5, 14.3 Hz, 1H), 6.54 (sextet, J = 7.0 Hz, 1H), 7.32–7.38 (m, 3H), 7.51–7.59
(m, 2H). 13C NMR (100 MHz, CDCl3, δ): –0.92 (CH3), 19.4 (CH3), 127.6 (CH),
127.8 (CH), 128.8 (CH), 133.7 (CH), 139.6 (C), 145.1 (CH). HRMS–EI (m/z):
[M]+ calcd for C11H16Si, 176.10213; found, 176.10222.
Preparation of (Z)‐(4‐(benzyloxy)but‐1‐en‐1‐yl)dimethyl(phenyl)silane
(1i).
To a suspension of NaH (60%, dispersion in Liquid Paraffin) (1.20 g, 30.0
mmol) in THF (20.0 mL), 3‐butyn‐1‐ol (1.51 mL, 20.0 mmol) was added
dropwise at 0 °C. After gas evaluation stopped, benzyl bromide (3.60 mL,
30.0 mmol) was added dropwise with stirring at 0 °C. The reaction mixture
was then warmed to room temperature and stirred for 4 h. After the reaction
was quenched by addition of NH4Cl aq. and extracted three times with Et2O.
The combined organic layer was dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude mixture was purified by
silica gel chromatography to afford the corresponding benzyl ether (2.88 g,
18.0 mmol, 90%) as a colorless oil.
In a vacuum dried 200 mL round bottomed flask, the obtained benzyl ether
(2.80 g, 17.5 mmol) was dissolved in dry THF (20.0 mL) and was cooled to –
SiMe2Ph
BnO
1iZ/E = >99:1
1. n-BuLi / Hex2. PhMe2SiCl
THF, 78 Crt
DIBAL
Et2O/Hexane0 Crt
BnO
SiMe2Ph
BnOHO
1. NaH2. BnBr
THF, 0 Crt
121
78 °C under nitrogen atmosphere. A hexane solution of n‐BuLi (1.62 M, 12.0
mL, 19.0 mmol) was then added dropwise for 10 min. After stirred for 1 h,
chlorodimethylphenylsilane was added dropwise and the reaction mixture
was stirred at –78 °C for 10 min. Then, it was warmed to room temperature
and stirred for 1 h. The reaction mixture was quenched by addition of
saturated NH4Cl aq. at 0 °C and extracted with Et2O three times. The
combined organic layer was then dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was purified by
flash column chromatography to obtain the corresponding silylacetylene
(4.53 g, 15.4 mmol, 88%) as a colorless oil.
In a 100 mL round bottomed flask, the obtained silylacetylene (2.94 g, 10.0
mmol) was dissolved in dry Et2O (10.0 mL) and mixture was cooled to 0 °C.
A hexane solution of DIBAL (1.0 M, 15.0 mL, 15.0 mmol) was then added
portion wise and the reaction mixture was warmed to room temperature.
After stirred for 20 h, the reaction mixture was quenched by addition of
NH4Cl aq. at 0 °C. After filtration, the mixture was extracted three times with
Et2O. The combined organic layer was dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was purified by
silica gel chromatography to obtain (Z)‐1i (Z/E = >99:1) (2.28 g, 7.70 mmol,
77%) as a colorless oil.
1H NMR (400 MHz, CDCl3, δ): 0.38 (s, 6H), 2.39 (q, J = 7.1 Hz, 2H), 3.42 (t, J
= 7.0 Hz, 2H), 4.43 (s, 2H), 5.76 (d, J = 14.3 Hz, 1H), 6.46 (dt, J = 7.2, 14.4 Hz,
1H), 7.27–7.36 (m, 8H), 7.51–7.57 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –
0.83 (CH3), 34.1 (CH2), 69.6 (CH2), 72.8 (CH2), 127.5 (CH), 127.6 (CH), 127.8
(CH), 128.4 (CH), 128.9 (CH), 129.2 (CH), 133.8 (CH), 138.5 (C), 139.5 (C), 146.5
(CH). 13C NMR (100 MHz, CDCl3, δ): –0.83 (CH3), 34.1 (CH2), 69.6 (CH2), 72.8
(CH2), 127.5 (CH), 127.6 (CH), 127.8 (CH), 128.4 (CH), 128.9 (CH), 129.2 (CH),
138.5 (C), 139.5 (C), 146.6 (CH). HRMS–ESI (m/z): [M+Na]+ calcd for
C19H24ONaSi, 319.14886; found, 319.14868.
122
Preparation of Alkenyl Alcohols.
The (Z)‐alkenyl alcohols for preparation of (Z)‐1h, 1j, 1l, 1m and 1n were
synthesized by DIBAL reduction of the corresponding silyl‐protected alkynyl
alcohols according to the procedure described above.
Preparation of
(Z)‐benzyl{3‐[(tert‐butyldimethylsilyl)oxy]prop‐1‐en‐1‐yl}dimethylsilane
(1h).
1h was prepared from the corresponding alkenyl alcohol by standard
silylation procedure.
1H NMR (400 MHz, CDCl3, δ): 0.05 (s, 6H), 0.10 (s, 6H), 0.89 (s, 9H), 2.15 (s,
2H), 4.07 (dd, J = 2.6, 6.0 Hz, 2H), 5.55 (dt, J = 1.6, 14.9 Hz, 1H), 6.41 (dt, J = 6.1,
14.9 Hz, 1H), 7.00 (d, J = 7.3 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.9 Hz,
2H). 13C NMR (100 MHz, CDCl3, δ): –5.1 (CH3), –1.8 (CH3), 18.3 (C), 26.0 (CH3),
26.5 (CH2), 63.7 (CH2), 124.1 (CH), 127.4 (CH), 128.1 (CH), 128.2 (CH), 139.7
(C), 149.1 (CH). HRMS–ESI (m/z): [M+Na]+ calcd for C18H32ONaSi2, 343.18839;
found, 343.18821.
Preparation of (Z)‐6‐(benzyldimethylsilyl)hex‐5‐en‐1‐yl benzoate (1j).
1j was prepared from the corresponding alkenyl alcohol by standard
acylation procedure.
1H NMR (400 MHz, CDCl3, δ): 0.10 (s, 6H), 1.49 (q, J = 7.9 Hz, 2H), 1.75
(quint, J = 7.3 Hz, 2H), 2.10 (q, J = 7.7 Hz, 2H), 2.16 (s, 2H), 4.3 (t, J = 6.8 Hz,
2H), 5.48 (d, J = 14.3 Hz, 1H), 6.33 (dt, J = 7.3, 14.5 Hz, 1H), 7.01 (d, J = 7.3 Hz,
2H), 7.06 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H),
SiMe2Bn
TBSO
1hZ/E = >99:1
SiMe2Bn
BzO
1jZ/E = >99:1
123
7.52–7.58 (m, 1H), 7.52–7.58 (m, 2H), 8.01–8.07 (m, 2H). 13C NMR (100 MHz,
CDCl3, δ): –1.7 (CH3), 25.9 (CH2), 26.6 (CH2), 28.3 (CH2), 33.1 (CH2), 64.6 (CH2),
123.9 (CH), 127.2 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 129.4 (CH), 130.3
(C), 132.7 (CH), 139.8 (C), 149.3 (CH), 166.4 (C). HRMS–ESI (m/z): [M+Na]+
calcd for C22H28O2NaSi, 375.17508; found, 375.17480.
Preparation of
(Z)‐dimethyl{4‐[(3‐methylbut‐2‐en‐1‐yl)oxy]but‐1‐en‐1‐yl}(phenyl)silane
(1l).
1l was prepared from the corresponding alkenyl alcohol and prenyl bromide
by standard etherification procedure.
1H NMR (400 MHz, CDCl3, δ): 0.39 (s, 6H), 1.65 (s, 3H), 1.73 (s, 3H), 2.35
(dq, J = 1.5, 7.3 Hz, 2H), 3.35 (t, J = 7.1 Hz, 2H), 3.87 (d, J = 7.3 Hz, 2H), 5.27–
5.34 (m, 1H), 5.75 (d, J = 14.3 Hz, 1H), 6.45 (dt, J = 7.3, 14.6 Hz, 1H), 7.30–7.37
(m, 3H), 7.51–7.58 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –1.04 (CH3), 17.8
(CH3), 25.6 (CH3), 34.0 (CH2), 67.1 (CH2), 69.2 (CH2), 121.1 (CH), 127.6 (CH),
128.7 (CH), 128.9 (CH), 133.5 (CH), 136.4 (C), 139.2 (C), 146.4 (CH). HRMS–ESI
(m/z): [M+Na]+ calcd for C17H26ONaSi, 297.16451; found, 297.16425.
Preparation of (Z)‐4‐[dimethyl(phenyl)silyl]but‐3‐en‐1‐yl
4‐cyanobenzoate (1m).
SiMe2Ph
O
Me
Me
1lZ/E = >99:1
SiMe2Ph
O
O
NC1m
Z/E = >99:1
124
1m was prepared from the corresponding alkenyl alcohol and
4‐cyanobenzoic acid by standard condensation procedure using
1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC).
1H NMR (400 MHz, CDCl3, δ): 0.40 (s, 6H), 2.53 (q, J = 7.0 Hz, 2H), 4.31 (t, J
= 6.6 Hz, 2H), 5.86 (d, J = 14.7 Hz, 1H), 6.46 (dt, J = 7.3, 14.5 Hz, 1H), 7.29–7.37
(m, 3H), 7.49–7.57 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H), 8.04–8.10 (m, 2H). 13C
NMR (100 MHz, CDCl3, δ): –1.12 (CH3), 32.6 (CH2), 64.6 (CH2), 116.1 (C), 117.8
(C), 127.7 (CH), 128.8 (CH), 129.8 (CH), 130.1 (CH), 130.4 (CH), 131.9 (CH),
133.4 (CH), 133.8 (C), 138.7 (C), 144.6 (CH), 164.5 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C20H21O2NNaSi, 358.12338; found, 358.12304.
Preparation of (Z)‐4‐[dimethyl(phenyl)silyl]but‐3‐en‐1‐yl
1‐methyl‐1H‐indole‐2‐carboxylate (1n).
1n was prepared from the corresponding alkenyl alcohol and
1‐methyl‐1H‐indole‐2‐carboxylic acid by standard condensation procedure
using 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC).
1H NMR (400 MHz, CDCl3, δ): 0.41 (s, 6H), 2.53 (dq, J = 1.5, 7.0 Hz, 2H),
4.05 (s, 3H), 4.28 (t, J = 7.8 Hz, 1H), 5.85 (dt, J = 1.4, 14.3 Hz, 2H), 6.51 (dt, J =
7.2, 14.4 Hz, 1H), 7.15 (ddd, J = 1.7, 6.3, 8.1 Hz, 1H), 7.24–7.27 (m, 1H), 7.29–
7.40 (m, 5H), 7.52–7.58 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3, δ): –0.91 (CH3), 31.5 (CH3), 32.9 (CH2), 63.6 (CH2), 110.17 (CH), 110.21
(CH), 120.5 (CH), 122.5 (CH), 124.9 (CH), 125.8 (C), 127.7 (C), 127.8 (CH), 128.9
(CH), 130.2 (CH), 133.6 (CH), 139.1 (C), 139.6 (C), 145.3 (CH), 162.0 (C).
HRMS–ESI (m/z): [M+Na]+ calcd for C22H25O2NNaSi, 386.15468; found,
386.15445.
SiMe2Ph
O
O
N
Me
1nZ/E = >99:1
125
Preparation of (E)‐trimethyl(4‐phenylbut‐1‐en‐1‐yl)silane (1a).
(E)‐1a was prepared by Bu3SnH‐mediated isomerization reaction of (Z)‐1a.2
1H NMR (400 MHz, CDCl3, δ): 0.04 (s, 9H), 2.37–2.45 (m, 2H), 2.71 (t, J = 8.2
Hz, 2H), 5.67 (dt, J = 1.6, 18.9 Hz, 1H), 6.08 (dt, J = 6.2, 18.6 Hz, 1H), 7.15–7.21
(m, 3H), 7.24–7.31 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –1.2 (CH3), 35.2
(CH2), 38.5 (CH2), 125.7 (CH), 128.2 (CH), 128.4 (CH), 130.4 (CH), 142.0 (C),
146.1 (CH). HRMS–EI (m/z): [M]+ calcd for C13H20Si, 204.13343; found,
204.13331.
SiMe3
Z/E = >99:1
(E)-1a
Ph
126
4. Characterization of Borylation Products.
The absolute configuration of the hydroboration product (S)‐3k was
determined by comparison of the optical rotation of the alcohol, which was
derived from (S)‐3k, and the literature value for (R)‐3k.11
(S)‐Trimethyl[4‐phenyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)butyl
]silane [(S)‐3a].
1H NMR (400 MHz, CDCl3, δ): –0.015 (s, 9H), 0.56 (dd, J = 5.9, 15.0, 1H),
0.78 (dd, J = 9.0, 14.8, 1H), 1.06–1.16 (m, 1H), 1.27 (s, 12H), 1.60–1.83 (m, 2H),
2.54–2.68 (m, 2H), 7.13–7.21 (m, 2H), 7.23–7.30 (m, 3H). 13C NMR (100 MHz,
CDCl3, δ): –0.94 (CH3), 17.4 (CH2), 18.1 (br, B–CH), 24.9 (CH3), 25.0 (CH3), 35.4
(CH2), 36.9 (CH2), 82.9 (C), 125.5 (CH), 128.2 (CH), 128.4 (CH), 143.0 (C).
HRMS–ESI (m/z): [M+Na]+ calcd for C19H33O2BNaSi, 354.22714; found,
354.22741. [α]D24.5 –19.50 (c 1.0 in CHCl3, 97% ee). The ee value was
determined by HPLC analysis (Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane
= 1/99, 0.5 mL/min, 40 °C, S isomer: tR = 31.44 min., R isomer: tR = 42.11 min.)
of the corresponding alcohol after NaBO3 oxidation of the borylated product
in comparison of the racemic sample.
(S)‐Dimethyl(phenyl)[4‐phenyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐
yl)butyl]silane [(S)‐3b].
1H NMR (400 MHz, CDCl3, δ): 0.26 (s, 6H), 0.81 (dd, J = 5.9, 15.0, 1H), 1.04
(dd, J = 8.8, 15.0, 1H), 1.10–1.19 (m, 1H), 1.21 (s, 12H), 1.59–1.80 (m, 2H), 2.48–
(S)-3a
SiMe3
Ph
BO
O
(S)-3b
SiMe2Ph
Ph
BO
O
127
2.62 (m, 2H), 7.10 (d, J = 7.0 Hz, 2H), 7.15 (q, J = 7.4 Hz, 1H), 7.24 (t, J = 7.5 Hz,
2H), 7.29–7.36 (m, 3H), 7.47–7.54 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –
2.49 (CH3), –2.28 (CH3), 16.4 (CH2), 18.0 (br, B–CH), 24.8 (CH3), 24.9 (CH3), 35.2
(CH2), 36.8 (CH2), 82.9 (C), 125.5 (CH), 127.6 (CH), 128.1 (CH), 128.3 (CH),
128.6 (CH), 133.6 (CH), 139.8 (C), 142.8 (C). HRMS–ESI (m/z): [M+Na]+ calcd
for C24H35O2BNaSi, 416.24279; found, 416.24263. [α]D24.5 –13.18 (c 1.1 in CHCl3,
94% ee). The ee value was determined by HPLC analysis (Daicel
CHIRALPAK® OZ‐3, 2‐PrOH/Hexane = 2/98, 0.5 mL/min, 40 °C, S isomer: tR
= 16.03 min., R isomer: tR = 16.93 min.) of the corresponding alcohol after
NaBO3 oxidation of the borylated product in comparison of the racemic
sample.
(S)‐Benzyldimethyl[4‐phenyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)
butyl]silane [(S)‐3c].
1H NMR (400 MHz, CDCl3, δ): –0.055 (s, 3H), –0.048 (s, 3H), 0.56 (dd, J = 5.5,
15.0, 1H), 0.80 (dd, J = 9.1, 15.0, 1H), 1.06–1.16 (m, 1H), 1.27 (s, 12H), 1.57–1.68
(m, 1H), 1.71–1.83 (m, 1H), 2.08 (s, 2H), 2.49–2.72 (m, 2H), 6.95–7.08 (m, 3H),
7.13–7.22 (m, 5H), 7.24–7.30 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –3.05
(CH3), –3.00 (CH3), 15.6 (CH2), 17.9 (br, B–CH), 24.8 (CH3), 24.9 (CH3), 25.9
(CH2), 35.3 (CH2), 37.0 (CH2), 82.9 (C), 123.7 (CH), 125.5 (CH), 127.98 (CH),
128.02 (CH), 128.2 (CH), 128.3 (CH), 140.3 (C), 142.8 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C25H37O2BNaSi, 430.25844; found, 430.25824. [α]D24.6 –12.73
(c 1.1 in CHCl3, 94% ee). The ee value was determined by HPLC analysis
(Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C, S
isomer: tR = 23.25 min., R isomer: tR = 31.05 min.) of the corresponding alcohol
after NaBO3 oxidation of the borylated product in comparison of the racemic
sample.
(S)-3c
SiMe2Bn
Ph
BO
O
128
(S)‐Methyldiphenyl[4‐phenyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl
)butyl]silane [(S)‐3d].
1H NMR (400 MHz, CDCl3, δ): 0.55 (s, 3H), 1.09–1.29 (m, 2H), 1.16 (s, 6H),
1.17 (s, 6H), 1.38 (dd, J = 8.4, 15.0, 1H), 1.56 (s, 12H), 1.58–1.79 (m, 2H), 2.44–
2.60 (m, 2H), 7.04 (m, 2H), 7.11–7.16 (m, 1H), 7.22 (t, J = 7.3 Hz, 2H), 7.28–7.38
(m, 6H), 7.48–7.54 (m, 4H). 13C NMR (100 MHz, CDCl3, δ): –3.94 (CH3), 14.7
(CH2), 18.0 (br, B–CH), 24.7 (CH3), 24.9 (CH3), 35.2 (CH2), 36.8 (CH2), 83.0 (C),
125.5 (CH), 127.68 (CH), 127.71 (CH), 128.1 (CH), 128.3 (CH), 129.0 (CH), 134.5
(CH), 134.6 (CH), 137.67 (C), 137.73 (C), 142.8 (C). HRMS–ESI (m/z): [M+Na]+
calcd for C29H37O2BNaSi, 478.25844; found, 478.25839. [α]D24.7 –36.07 (c 1.4 in
CHCl3, 91% ee). The ee value was determined by HPLC analysis (Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane =3/97, 0.5 mL/min, 40 °C, S isomer: tR
= 52.93 min., R isomer: tR = 40.27 min.) of the corresponding alcohol after
NaBO3 oxidation of the borylated product in comparison of the racemic
sample.
(S)‐Dimethyl(phenyl)[2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)propyl]
silane [(S)‐3e].
1H NMR (400 MHz, CDCl3, δ): 0.270 (s, 3H), 0.273 (s, 3H), 0.68 (dd, J = 6.6,
14.6, 1H), 0.99 (d, J = 7.3, 3H), 1.02–1.16 (m, 2H), 1.20 (s, 12H), 7.29–7.35 (m,
3H), 7.49–7.55 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): –2.32 (CH3), –2.28
(CH3), 12.0 (br, B–CH), 18.8 (CH2), 19.4 (CH3), 24.6 (CH3), 24.7 (CH3), 82.7 (C),
127.5 (CH), 128.5 (CH), 133.5 (CH), 140.0 (C). HRMS–ESI (m/z): [M+Na]+ calcd
for C17H29O2BNaSi, 327.19275; found, 327.19256. [α]D22.8 +13.50 (c 1.0 in CHCl3,
(S)-3d
SiMePh2
Ph
BO
O
SiMe2Ph
Me
B
(S)-3e
O
O
129
94% ee). The ee value was determined by HPLC analysis (Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S isomer: tR
= 39.57 min., R isomer: tR = 42.13 min.) of the corresponding alcohol after
NaBO3 oxidation of the borylated product in comparison of the racemic
sample.
(S)‐Benzyldimethyl[2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)hexyl]sil
ane [(S)‐3f].
1H NMR (400 MHz, CDCl3, δ): –0.052 (s, 3H), –0.047 (s, 3H), 0.50 (dd, J = 5.7,
15.2, 1H), 0.75 (dd, J = 9.2, 15.0, 1H), 0.88 (t, J = 7.14, 3H), 0.98–1.09 (m, 1H),
1.19–1.49 (m, 6H), 1.24 (s, 12H), 2.08 (s, 2H), 7.00 (d, J = 7.3 Hz, 2H), 7.05 (t, J =
7.5 Hz, 1H), 7.19 (t, J = 7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ): –3.1 (CH3),
14.1 (CH3), 15.8 (CH2), 18.0 (br, B–CH), 22.9 (CH2), 24.8 (CH3), 24.9 (CH3), 26.0
(CH2), 31.2 (CH2), 34.7 (CH2), 82.8 (C), 123.7 (CH), 128.0 (CH), 128.1 (CH),
140.5 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C21H37O2BNaSi, 382.25844;
found, 382.25829. [α]D24.8 +7.00 (c 1.0 in CHCl3, 94% ee). The ee value was
determined by HPLC analysis (Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane
= 0.5/99.5, 0.5 mL/min, 40 °C, S isomer: tR = 28.07 min., R isomer: tR = 31.60
min.) of the corresponding alcohol after NaBO3 oxidation of the borylated
product in comparison of the racemic sample.
(S)‐Benzyl[3‐cyclohexyl‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)prop
yl]dimethylsilane [(S)‐3g].
SiMe2BnB
Me
O
O(S)-3f
SiMe2BnB
(S)-3g
O
O
130
1H NMR (400 MHz, CDCl3, δ): –0.048 (s, 3H), –0.045 (s, 3H), 0.49 (dd, J = 5.7,
15.2, 1H), 0.69 (dd, J = 8.1, 15.0, 1H), 0.76–0.92 (m, 2H), 1.06–1.43 (m, 7H), 1.24
(s, 12H), 1.58–1.80 (m, 5H), 2.08 (s, 2H), 7.00 (d, J = 7.0 Hz, 2H), 7.05 (t, J = 7.5
Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ): –2.98 (CH3), –
2.93 (CH3), 15.4 (br, B–CH), 15.9 (CH2), 24.9 (CH3), 26.1 (CH2), 26.5 (CH2), 26.7
(CH2), 33.3 (CH2), 33.7 (CH2), 37.0 (CH), 42.6 (CH2), 82.8 (C), 123.7 (CH), 128.0
(CH), 128.1 (CH), 140.5 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C24H41O2BNaSi, 422.28974; found, 422.28940. [α]D21.9 –20.42 (c 1.2 in CHCl3,
89% ee). The ee value was determined by HPLC analysis (Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min, 40 °C, S
isomer: tR = 25.44 min., R isomer: tR = 27.91 min.) of the corresponding alcohol
after NaBO3 oxidation of the borylated product in comparison of the racemic
sample.
(S)‐Benzyl{3‐[(tert‐butyldimethylsilyl)oxy]‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐diox
aborolan‐2‐yl)propyl}dimethylsilane [(S)‐3h].
1H NMR (400 MHz, CDCl3, δ): –0.048 (s, 3H), –0.037 (s, 3H), 0.023 (s, 3H),
0.029 (s, 3H), 0.51 (dd, J = 4.8, 15.0, 1H), 0.67 (dd, J = 9.9, 15.0, 1H), 0.88 (s, 9H),
1.20–1.32 (m, 1H), 1.24 (s, 12H), 2.09 (s, 2H), 3.59 (d, J = 7.0 Hz, 2H), 6.99 (d, J
= 7.3 Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H). 13C NMR (100
MHz, CDCl3, δ): –5.39 (CH3), –3.19 (CH3), –3.06 (CH3), 11.7 (CH2), 18.3 (C),
22.3 (br, B–CH), 24.9 (CH3), 25.86 (CH2), 25.94 (CH3), 67.6 (CH2), 82.9 (C), 123.7
(CH), 128.00 (CH), 128.03 (CH), 140.4 (C). HRMS–ESI (m/z): [M+H]+ calcd for
C24H46O3BSi2, 448.31094; found, 448.31116. [α]D23.1 –10.56 (c 0.9 in CHCl3, 97%
ee). The ee value was determined by HPLC analysis (Daicel CHIRALPAK®
OD‐3, 2‐PrOH/Hexane = 0/100, 0.5 mL/min, 40 °C, S isomer: tR = 22.11 min., R
isomer: tR = 28.00 min.) of the corresponding alcohol after NaBO3 oxidation of
SiMe2BnB
TBSO
(S)-3h
O
O
131
the borylated product in comparison of the racemic sample.
(S)‐[4‐(Benzyloxy)‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)butyl]dime
thyl(phenyl)silane [(S)‐3i].
1H NMR (400 MHz, CDCl3, δ): 0.27 (s, 6H), 0.74 (dd, J = 6.0, 15.2, 1H), 1.00
(dd, J = 8.4, 15.0, 1H), 1.12–1.19 (m, 1H), 1.15 (s, 12H), 1.61–1.81 (m, 2H), 3.39
(t, J = 7.0 Hz, 2H), 4.45 (s, 2H), 7.21–7.34 (m, 8H), 7.47–7.54 (m, 2H). 13C NMR
(100 MHz, CDCl3, δ): –2.49 (CH3), –2.30 (CH3), 14.9 (br, B–CH), 16.3 (CH2),
24.66 (CH3), 24.74 (CH3), 34.3 (CH2), 69.3 (CH2), 72.6 (CH2), 82.8 (C), 127.3
(CH), 127.5 (CH), 128.1 (CH), 128.6 (CH), 133.5 (CH), 138.6 (C), 139.8 (C).
HRMS–ESI (m/z): [M+Na]+ calcd for C18H37O3BNaSi, 446.25335; found,
446.25406. [α]D22.3 –30.00 (c 1.2 in CHCl3, 89% ee). The ee value was
determined by HPLC analysis (Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane
= 0.5/99.5, 0.5 mL/min, 40 °C, S isomer: tR = 48.27 min., R isomer: tR = 56.16
min.) of the corresponding alcohol after NaBO3 oxidation of the borylated
product in comparison of the racemic sample.
(S)‐6‐(Benzyldimethylsilyl)‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)h
exyl benzoate [(S)‐3j].
1H NMR (400 MHz, CDCl3, δ): –0.047 (s, 3H), –0.039 (s, 3H), 0.50 (dd, J = 5.9,
15.0, 1H), 0.77 (dd, J = 9.2, 15.0, 1H), 1.02–1.11 (m, 1H), 1.22 (s, 12H), 1.35–1.54
(m, 4H), 1.69–1.80 (m, 2H), 2.08 (s, 2H), 4.30 (t, J = 6.6 Hz, 2H), 6.99 (d, J = 7.3
Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H),
SiMe2Ph
BnO
B
(S)-3i
O
O
SiMe2BnB
BzO
(S)-3j
O
O
132
7.55 (tt, J = 1.6, 7.6 Hz, 1H), 8.01–8.06 (m, 2H). 13C NMR (100 MHz, CDCl3, δ):
–2.88 (CH3), –2.84 (CH3), 15.9 (CH2), 18.0 (br, B–CH), 24.9 (CH3), 25.0 (CH3),
25.6 (CH2), 26.1 (CH2), 29.1 (CH2), 34.8 (CH2), 65.2 (CH2), 83.1 (C), 123.9 (CH),
128.17 (CH), 128.22 (CH), 128.4 (CH), 129.6 (CH), 130.6 (C), 132.9 (CH), 140.6
(C), 166.7 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C28H41O4BNaSi, 502.27957;
found, 502.27982. [α]D24.3 –1.15 (deg cm3 g‐1 dm‐1) (c 1.3 in CHCl3, 90% ee). The
ee value was determined by HPLC analysis (Daicel CHIRALPAK® OZ‐3,
2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S isomer: tR = 21.77 min., R isomer:
tR = 25.12 min.) of the corresponding alcohol after NaBO3 oxidation of the
borylated product in comparison of the racemic sample.
(S)‐[5‐Chloro‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pentyl]dimethy
l(phenyl)silane [(S)‐3k].3
1H NMR (400 MHz, CDCl3, δ): 0.28 (s, 6H), 0.72 (dd, J = 5.1, 14.3, 1H), 0.96–
1.13 (m, 2H), 1.19 (s, 12H), 1.40–1.56 (m, 2H), 1.64–1.80 (m, 2H), 3.42 (t, J = 6.8
Hz, 2H), 7.29–7.36 (m, 3H), 7.47–7.55 (m, 2H). 13C NMR (100 MHz, CDCl3, δ):
–2.58 (CH3), –2.34 (CH3), 16.5 (CH2), 17.4 (br, B–CH), 24.7 (CH3), 24.8 (CH3),
31.82 (CH2), 31.84 (CH2), 45.1 (CH2), 82.9 (C), 127.6 (CH), 128.7 (CH), 133.5
(CH), 139.6 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C19H32O2BClNaSi,
388.18817; found, 388.18872. [α]D20.2 +4.12 (c 0.85 in CHCl3, 95% ee). The ee
value was determined by HPLC analysis (Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min, 40 °C, S isomer: tR = 45.41 min., R
isomer: tR = 50.88 min.) of the corresponding alcohol after NaBO3 oxidation of
the borylated product in comparison of the racemic sample.
SiMe2PhB
Cl
O
O(S)-3k
133
(S)‐Dimethyl{4‐[(3‐methylbut‐2‐en‐1‐yl)oxy]‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dio
xaborolan‐2‐yl)butyl}(phenyl)silane [(S)‐3l].
1H NMR (400 MHz, CDCl3, δ): 0.27 (s, 6H), 0.75 (dd, J = 5.9, 15.0, 1H), 1.01
(dd, J = 8.8, 15.0, 1H), 1.08–1.16 (m, 1H), 1.19 (s, 12H), 1.59–1.80 (m, 2H), 1.64
(s, 3H), 1.72 (s, 3H), 3.35 (t, J = 7.3 Hz, 2H), 3.89 (d, J = 7.3 Hz, 2H), 5.28–5.35
(m, 1H), 7.30–7.35 (m, 3H), 7.48–7.55 (m, 2H). 13C NMR (100 MHz, CDCl3, δ):
–2.54 (CH3), –2.39 (CH3), 14.8 (br, B–CH), 16.3 (CH2), 17.8 (CH3), 24.6 (CH3),
24.7 (CH3), 25.7 (CH3), 34.4 (CH2), 67.0 (CH2), 69.2 (CH2), 82.7 (C), 121.5 (CH),
127.5 (CH), 128.5 (CH), 133.5 (CH), 136.0 (C), 139.7 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C23H39O3BNaSi, 424.26900; found, 424.26926. [α]D24.0 +3.75 (c
1.2 in CHCl3, 88% ee). The ee value was determined by HPLC analysis
(Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S
isomer: tR = 37.95 min., R isomer: tR = 40.00 min.) of the corresponding alcohol
after NaBO3 oxidation of the borylated product in comparison of the racemic
sample.
(S)‐4‐[Dimethyl(phenyl)silyl]‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl
)butyl 4‐cyanobenzoate [(S)‐3m].
1H NMR (400 MHz, CDCl3, δ): 0.29 (s, 6H), 0.81 (dd, J = 6.0, 15.2, 1H), 1.06
(dd, J = 8.8, 15.0, 1H), 1.17–1.29 (m, 1H), 1.20 (s, 12H), 1.73–1.93 (m, 2H), 4.24–
SiMe2Ph
O
B
Me
Me
(S)-3l
O
O
SiMe2Ph
O
B
O
NC
(S)-3m
O
O
134
4.38 (m, 2H), 7.27–7.33 (m, 3H), 7.47–7.54 (m, 2H), 7.71 (d, J = 8.8, 2H), 8.05 (d,
J = 8.4, 2H). 13C NMR (100 MHz, CDCl3, δ): –2.61 (CH3), –2.27 (CH3), 14.4 (br,
B–CH), 24.65 (CH2), 24.74 (CH3), 32.9 (CH2), 64.9 (CH2), 83.1 (C), 116.0 (CH),
117.9 (C), 127.6 (CH), 128.7 (CH), 130.0 (CH), 132.0 (CH), 133.5 (CH), 134.2 (C),
139.5 (C), 164.7 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C26H34O4NBNaSi,
485.22787; found, 485.22816. [α]D24.1 +17.08 (c 1.2 in CHCl3, 95% ee). The ee
value was determined by HPLC analysis (Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S isomer: tR = 18.61 min., R isomer:
tR = 19.75 min.) of the corresponding alcohol after NaBO3 oxidation of the
borylated product in comparison of the racemic sample.
(S)‐4‐[Dimethyl(phenyl)silyl]‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl
)butyl‐1‐methyl‐1H‐indole‐2‐carboxylate [(S)‐3n].
1H NMR (400 MHz, CDCl3, δ): 0.30 (s, 3H), 0.31 (s, 3H), 0.79–0.88 (m, 1H),
1.02–1.11 (m, 1H) 1.20 (s, 12H), 1.23–1.34 (m, 1H), 1.74–1.95 (m, 2H), 4.04 (s,
3H), 4.20–4.35 (m, 2H), 7.11–7.18 (m, 1H), 7.21–7.25 (m, 1H), 7.27–7.39 (m, 5H),
7.49–7.55 (m, 2H), 7.67 (d, J = 8.4, 1H). 13C NMR (1,00 MHz, CDCl3, δ): –2.49
(CH3), –2.27 (CH3), 14.6 (br, B–CH), 16.2 (CH2), 24.7 (CH3), 24.8 (CH3), 31.5
(CH3), 33.1 (CH2), 63.8 (CH2), 83.0 (C), 110.1 (CH), 120.3 (CH), 122.4 (CH),
124.7 (CH), 125.8 (C), 127.6 (CH), 127.9 (C), 128.7 (CH), 133.5 (CH), 139.5 (C),
162.1 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C28H38O4NBNaSi, 513.25917;
found, 513.26000. [α]D23.5 –3.82 (c 1.7 in CHCl3, 96% ee). The ee value was
determined by HPLC analysis (Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane
= 3/97, 0.5 mL/min, 40 °C, S isomer: tR = 13.07 min., R isomer :tR = 16.15 min.)
of the corresponding alcohol after NaBO3 oxidation of the borylated product
in comparison of the racemic sample.
SiMe2Ph
O
B
O
N
Me
(S)-3n
O
O
135
5. Stepwise Transformations of Hydroboration Products.
Experimental Procedure for the Synthesis of Chiral 1,2‐Diol (S)‐5.2
In a reaction vial, NaBO3•4H2O (184.6 mg, 1.20 mmol) was dissolved in
THF/H2O (1:1, 4.00 mL). (S)‐3j (144.2 mg, 0.30 mmol) was then added at room
temperature. After stirred for 12 h, the reaction mixture was extracted three
times with EtOAc, dried over MgSO4, and filtered. The crude material was
purified by flash column chromatography to obtain the corresponding
alcohol (92.3 mg, 0.250 mmol, 83%) as a colorless oil.
A THF solution of tetrabutylanmonium fluoride (1.0 M, 2.00 mL, 2.00
mmol) was added to a solution of the alcohol (92.3 mg, 0.25 mmol) in THF
(3.50 mL) with stirring at room temperature. After 30 min, KHCO3 (100.1 mg,
1.00 mmol), MeOH (2.00 mL) and 30% H2O2 (1.00 mL) were successively
added to the reaction mixture. After 30 min, the reaction mixture was diluted
with water, extracted with three times of CHCl3, dried over MgSO4, and
filtered. After evaporation, the crude product was used in the next step
without further purification.
In a reaction vial, the crude mixture of the diol and
dimethylaminopyridine (DMAP) (30.5 mg, 0.25 mmol) were dissolved in
CH2Cl2 (1.00 mL). After addition of pyridine (59.4 μL, 0.75 mmol), the
reaction mixture was cooled to 0 °C. Acetyl chloride (53.3 μL, 0.75 mmol) was
added dropwise to the mixture and stirred for 1 h. The reaction was
quenched by addition of water, extracted with Et2O there times. The
combined organic layer was then dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was purified by
flash column chromatography to give the diol (S)‐5 (62.1 mg, 0.19 mmol, 77%,
2 steps) as a colorless oil. (64% 3 steps)
SiMe2Bn(pin)B
BzO
90% ee(S)-3j
1. NaBO3/4H2O2. TBAF, H2O2 KHCO3, MeOH
OAcAcO
BzO
(S)-590% ee
3.AcCl, pyridine DMAP, DCM
136
1H NMR (400 MHz, CDCl3, δ): 1.42–1.59 (m, 2H), 1.60–1.73 (m, 2H), 1.74–
1.89 (m, 2H), 2.057 (s, 3H), 2.065 (s, 3H), 4.05 (dd, J = 6.4, 12.3 Hz, 2H), 4.24
(dd, J = 3.3, 12.1 Hz, 2H), 4.32 (t, J = 6.8 Hz, 2H), 5.07–5.14 (m, 1H), 7.45 (t, J =
7.7 Hz, 2H), 7.56 (tt, J = 1.5, 7.6 Hz, 1H), 8.00–8.06 (m, 2H). 13C NMR (100
MHz, CDCl3, δ): 20.7 (CH3), 21.0 (CH3), 21.7 (CH2), 28.4 (CH2), 30.2 (CH2), 64.4
(CH2), 64.9 (CH2), 71.1 (CH3), 128.3 (CH), 129.4 (CH), 130.2 (C), 132.8 (CH),
166.5 (C), 170.5 (C), 170.7 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C17H22O6Na,
345.13086; found, 345.13062. [α]D24.7 –9.23 (c 1.3 in CHCl3, 90% ee). The ee
value was determined by HPLC analysis (Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C, (S)‐5: tR = 46.08 min., (R)‐5: tR =
49.87 min.).
Experimental Procedure for the Synthesis of Chiral 1,2‐Aminoalcohol
(S)‐6.2
In an oven‐dried reaction vial, CH2Cl2 solution of BCl3 (1.00 M, 2.00 mL,
2.00 mmol) was added under nitrogen atmosphere. (S)‐3f (144.2 mg, 0.40
mmol) was added to the reaction vial with stirring at room temperature.
After 4 h, the volatile materials were removed under reduced pressure, and
dry CH2Cl2 (2.50 mL) was added to the resultant product. The reaction vial
was cooled to 0 °C, and benzyl azide (159.8 mg, 1.20 mmol) was added to the
mixture. After stirred for 15 h at 0 °C, the reaction mixture was quenched by
adding NaOH aq. (2.0 M), extracted three times with CHCl3, dried over
MgSO4, and filtered. The crude material was then purified by flash column
chromatography to obtain the corresponding amine (108.7 mg, 0.32 mmol,
80%) as a yellow oil.
A THF solution of tetrabutylanmonium fluoride (1.0 M, 2.56 mL, 2.56
mmol) was added to a solution of the amine (108.7 mg, 0.32 mmol) in THF
SiMe2Bn(pin)B
Me
(S)-3f94% ee
OHBnHN
Me
(S)-693% ee
1. BCl3, CH2Cl22. BnN3, CH2Cl2
3. TBAF, H2O2 KHCO3, MeOH
137
(4.80 mL) with stirring at room temperature. After 30 min, KHCO3 (128.1 mg,
1.28 mmol), MeOH (2.50 mL) and 30% H2O2 (1.30 mL) were successively
added to the reaction mixture. After 30 min, the reaction mixture was diluted
with water, extracted with three times of CHCl3, dried over MgSO4, and
filtered. After evaporation, the crude product was then purified by flash
column chromatography to obtain the aminoalcohol (S)‐6 (51.1 mg, 0. 25
mmol, 77%) as a white solid. (62%, 3 steps)
1H NMR (400 MHz, CDCl3, δ): 0.90 (t, J = 7.1 Hz, 3H), 1.21–1.59 (m, 6H),
2.65–2.73 (m, 1H), 3.32 (dd, J = 6.2, 11.0 Hz, 3H), 3.66 (dd, J = 4.0, 11.0 Hz, 1H),
3.80 (q, J = 13.4 Hz, 2H), 7.22–7.37 (m, 5H). 13C NMR (100 MHz, CDCl3, δ):
14.1 (CH3), 23.0 (CH2), 28.3 (CH2), 31.3 (CH2), 51.0 (CH2), 58.4 (CH3), 62.9 (CH2),
127.3 (CH), 128.3 (CH), 128.6 (CH), 140.1 (C). HRMS–ESI (m/z): [M+H]+ calcd
for C13H22ON, 208.16959; found, 208.16965. [α]D24.7 +5.63 (c 0.8 in CHCl3, 93%
ee).
The ee value was determined by HPLC analysis (Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C, (S)‐6: tR = 15.85 min., (R)‐6: tR =
17.19 min.).
138
References and Notes
(1) (a) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine
and Materials, 2 nd revised ed.; Hall, D. G., Ed.; Wiley‐VCH: Weinheim,
2011. (b) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature
2008, 456, 778.
(2) The early example of copper(I)‐catalyzed borylation reaction, see:(a) Ito,
H.; Ito, H.; Yamanaka, H.; Yamanaka, H.; Tateiwa, J.; Tateiwa, J.; Hosomi,
A.; Hosomi, A. Tetrahedron. Lett. 2000, 41, 6821. (b) Takahashi, K.; Ishiyama,
T.; Miyaura, N. Chem. Lett. 2000, 982.
(3) For Ito and Sawamura’s studies on copper(I)‐catalyzed borylation
reactions, see: (a) Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc.
2005, 127, 16034. (b) Ito, H.; Ito, S.; Ito, S.; Sasaki, Y.; Sasaki, Y.; Matsuura,
K.; Matsuura, K.; Sawamura, M.; Sawamura, M. J. Am. Chem. Soc. 2007, 129,
14856. (c) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M.
Angew. Chem., Int. Ed. 2008, 47, 7424. (d) Ito, H.; Ito, H.; Sasaki, Y.; Sasaki,
Y.; Sawamura, M.; Sawamura, M. J. Am. Chem. Soc. 2008, 130, 15774. (e)
Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132,
1226. (f) Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am.
Chem. Soc. 2010, 132, 11440. (g) Ito, H.; Okura, T.; Matsuura, K.; Sawamura,
M. Angew. Chem., Int. Edit. 2010, 49, 560. (h) Ito, H.; Toyoda, Sawamura, M.
J. Am. Chem. Soc. 2010, 132, 5990. (i) Ito, H.; Kunii, S.; Sawamura, M. Naure.
Chem. 2010, 2, 972. (j) Sasaki, Y.; Sasaki, Y.; Horita, Y.; Horita, Y.; Zhong,
C.; Zhong, C.; Sawamura, M.; Sawamura, M.; Ito, H.; Ito, H. Angew. Chem.,
Int. Ed. 2011, 50, 2778.
(4) For selected examples of copper(I)‐catalyzed asymmetric hydroboration,
see: (a) Lee, J.‐E.; Lee, J.‐E.; Yun, J.; Yun, J. Angew. Chem., Int. Ed. 2008, 47,
145. (b) Lillo, V.; Prieto, A.; Bonet, A.; Diaz‐Requejo, M. M.; Ramirez, J.;
Perez, P. J.; Fernandez, E. Organometallics 2009, 28, 659. (c) Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160. (d) Noh, D.; Chea, H.; Ju,
J.; Yun, J. Angew. Chem. Int. Ed. 2009, 48, 6062. (e) Chen, I.‐H.; Yin, L.; Itano,
139
W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 11664. (f) OʹBrien,
J. M.; Lee, K.‐S.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10630. (g)
Moure, A. L.; Gómez Arrayás, R.; Carretero, J. C. Chem Commun. 2011, 47,
6701. (h) Solé, C.; Solé, C.; Whiting, A.; Whiting, A.; Gulyás, H.; Gulyás,
H.; Fernandez, E.; Fernandez, E. Adv. Synth. Catal. 2011, 353, 376. (i)
Corberán, R.; Mszar, N. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2011, 50,
7079. (j) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894. (k)
Feng, X.; Feng, X.; Jeon, H.; Jeon, H.; Yun, J.; Yun, J. Angew. Chem., Int. Ed.
2013, 52, 3989.
(5) For selected examples of transition‐metal‐catalyzed asymmetric
hydroboration, see:(a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc.
1989, 111, 3426. (b) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc.
2003, 125, 7198. (c) Crudden, C. M.; Hleba, Y. B.; Chen, A. C. J. Am. Chem.
Soc. 2004, 126, 9200. (d) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
3160. (e) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem. Int. Ed. 2009, 48,
6062. (g) Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008,
130, 3734.
(6) Copper(I)‐catalyzed enantioselective borylative aldol cyclizations has been
reported: Burns, A. R.; Solana González, J.; Lam, H. W. Angew. Chem., Int.
Ed. 2012, 51, 10827.
(7) Copper(I)‐catalyzed aminoboration has been reported: Matsuda, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2013, 135, 4934.
(8) (a) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A. Org.
Lett. 2000, 2, 385. (b) Murakami, M.; Suginome, M.; Fujimoto, K.;
Nakamura, H.; Andersson, P.G.; Ito, Y. J. Am. Chem. Soc. 1993, 115, 6487.
(9) Brinkmann, A. E.; Berger, Susan.; Brauman, I. J. J. Am. Chem. Soc. 1994, 116,
8304.
(10)For the rate accelaration effect of proton sources in the copper‐catalyzed
borylation, see: Mun, S.; Lee, J.‐E.; Yun, J. Org. Lett. 2006, 8, 4887.
(11)Meng, F.; Jang, H.; Hoveyda, A. H. Chem. Euro. J. 2013, 19, 3204.
140
(12)(a) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934–
11935. (b) Imamoto, T.; Tamura, K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.;
Yoshida, K.; Yanagisawa, A.; Gridnev, I. D. J. Am. Chem. Soc. 2012, 134,
1754.
(13)(a) Dang, L.; Zhao, H.; Lin, Z.; Marder, T. B. Organometallics 2008, 27, 1178.
(b) Dang, L.; Lin, Z. Y.; Marder, T. B. Chem. Commun. 2009, 3987.
(14)Ligand effect on the addition of borylcopper(I) complex to unactivated
terminal alkenes has been discussed based on DFT caluculations
(B3PW91/cc‐pVDZ), see: Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem.
Soc. 2013, 135, 2625.
(15)(a) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890. (b) Yang, C.‐T.; Zhang,
Z.‐Q.; Tajuddin, H.; Wu, C.‐C.; Liang, J.; Liu, J.‐H.; Fu, Y.; Czyzewska, M.;
Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2011, 51, 528. For
related copper(I)‐catalyzed boryl substitution of ary halides: (c) Kleeberg,
C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem., Int. Ed. 2009, 48, 5350.
(16)Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem. 1989, 54,
5930.
(17)Hupe, E.; Marek, I.; Knochel, P. Org. Lett. 2002, 4, 2861.
(18)The reaction of (Z)‐1a with 2 in the presence of 5 mol % of CuCl/PPh3
catalyst gave 16 % of (rac)‐3a unedr the same conditions for Table 1. Use of
IMes resulted in 80% yield of (rac)‐3a.
(19)Gaussian 09, Revision C.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J.
A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
141
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.;
Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D.
J. Gaussian, Inc., Wallingford CT, 2009.
142
Chapter 4.
Copper(I)‐Catalyzed Enantioselective Nucleophilic
Borylation of Aldehydes
143
Abstract
The first catalytic enantioselective nucleophilic borylation of a C=O
double bond has been achieved. A series of aldehydes reacted with a diboron
reagent in the presence of a copper(I)/DTBM‐SEGPHOS complex catalyst
using MeOH as a proton source to give the corresponding optically active
‐alkoxyorganoboronate esters with excellent enantioselectivities.
Furthermore, the products could be readily converted to the corresponding
functionalized chiral alcohol derivatives through stereospecific CC bond
forming reactions involving the stereogenic CB bond.
Introduction
Enantioenriched organoboronate esters are a particularly important class of
chiral compounds that have attracted considerable interest from researchers
working in a variety of different fields because of their broad range of
synthetic and medicinal applications.1 Significant research efforts have
recently been focused on the development of catalytic enantioselective
strategies for the construction of stereogenic CB bonds.2 In particular, copper(I)‐catalyzed enantioselective borylation reactions with diboron
reagents have emerged as efficient methods for the synthesis of chiral
organoboronates with high enantioselectivity.3‐5 Despite this recent progress
in borylation chemistry, there have been no reports in the literature
pertaining to the catalytic enantioselective borylation of carbon‐oxygen
double bonds.6,7 The development of a novel transformation of this type
would allow for the direct synthesis of chiral α‐alkoxyorganoboronate esters,
which could be used as chiral building blocks in organic synthesis and
medicinal chemistry.8 Molander et al.9 reported the successful development
of a stereospecific cross‐coupling reaction between chiral potassium
‐(benzyloxy)alkyltrifluoroborates and aryl halides. It is noteworthy,
however, that this pioneering work required the synthesis of an
enantiomerically enriched α‐alkoxyorganotrifluoroborate through multiple
144
synthetic transformations as well as the addition of a stoichiometric amount
of a chiral auxiliary.10 Thus, the development of a new method for the
catalytic enantioselective addition of boron nucleophiles to carbonyl
compounds to give chiral ‐alkoxyorganoboronate esters is therefore highly
beneficial.9, 11‐13
The first of these pioneering studies towards the catalytic borylation of
aldehydes was reported by Sadighi et al.12 in 2006, where an N‐heterocyclic
carbine(NHC)/copper(I) complex was found to catalyze the diboration of
both aliphatic and aromatic aldehydes (Scheme 1a). More recently, Molander
et al.9 developed a process for the copper(I)‐catalyzed monoborylation of
aldehydes using methanol as a proton source (Scheme 1b). Despite the
considerable progress made by these researchers, their works have not yet
been extended to the development of enantioselective processes via the
introduction of a chiral ligand.
Scheme 1. Non‐enantioselective Borylation of Aldehydes by Copper(I)
Catalysis
Herein, the author reports the development of the first catalytic
enantioselective borylation of aldehydes with a diboron compound to afford
the corresponding chiral α‐alkoxyorganoboronate esters using a
copper(I)/DTBM‐SEGPHOS complex catalyst (Scheme 2). This new reaction
exhibited excellent enantioselectivities and a broad substrate scope, and the
products could be converted to the corresponding enantiomerically enriched
R H
O
R = Alkyl, Aryl
cat. Cu(I) / ICy
benzene, rtB B
O
O O
O+
R B(pin)
OB(pin)
cat. Cu(I) / ICy
alkoxide base, 2MeOH, toluene
R B(pin)
OH
a) Diborylation J. P. Sadighi (2006)
b) Monoborylation G. A. Molander (2012)
1 2
KHF2
R BF3K
OH
racemic
racemic
R H
O
R = Alkyl, Aryl1
145
secondary alcohol derivatives through stereospecific CC bond forming
reactions.
Scheme 2. The First Enantioselective Broyaltion of a C=O Double Bond
Results and Discussion
Initial efforts in this study were focused on the development of a suitable
method for the purification and isolation of ‐hydroxyalkylboronate esters,
which are generally unstable to purification by column chromatography over
silica gel. Although the borylated products can be isolated by converting
them to the corresponding organotrifluoroborates, it can be difficult to
determine the ee values of these products by HPLC analysis.9 With this in
mind, it would be a critical requirement of any newly developed
enantioselective process to incorporate an isolation procedure that would
allow for HPLC analysis of the resulting products. We have attempted
various etherifications of the hydroxy group in the product resulting from
the borylation of aliphatic aldehyde 1a in the presence of a copper(I)/ICy
complex catalytic system, but yields were poor (Table 1, entries 1 3, <33%
yields).14 Other protection strategies, including the esterification and
carbamylation under various conditions were investigated, but resulted in
low isolated yields (Table 1, entries 4 7, <22% yields). Pleasingly, however,
the desired product could be obtained in sufficiently good yield (Table 1,
entry 8, 64% yield) when a standard silyl protection protocol was used to
protect the hydroxyl group of the crude product. Furthermore, the resulting
silyl ether products were suitable for HPLC analysis.15
R H
O
R = Alkyl, ArylR H
B(pin)R3SiO5 mol % CuCl / L* B2(pin)2 (1.5 equiv)
K(O-t-Bu) (20 mol %)MeOH (2.0 equiv)THF then silylation
L* = (R)-DTBM-SEGPHOS
up to 82% yieldup to 99% ee
O
O
O
O
P
P
tBu
OMe
tButBu
OMetBu
2
2
Enantioselective Nucleophilic Borylation
146
Table 1. Investigation of the Protecting Group for Isolating the Aldehyde
Borylation Product
With an optimized procedure in hand, the author proceeded to investigate
the enantioselective borylation process using chiral bisphosphine ligands
(Table 2). The reaction of aliphatic aldehyde 1a with bis(pinacolato)diboron
(2) (1.0 equiv) in the presence of CuCl/(R)‐DTBM‐SEGPHOS (5 mol %),
K(O‐t‐Bu) (10 mol %) and MeOH (2.0 equiv), which was used as a proton
source, in THF at 30 °C (Table 2) afforded the desired product (S)‐3a in good
yield (72%) with excellent enantioselectivity (96% ee) via the silyl protection
of the crude α‐hydroxyalkylboronate (Table 2, entry 1). The use of the less
sterically encumbered SEGPHOS type ligands led to a significant decrease in
the enantioselectivity of the reaction (Table 2, entries 2 and 3). The use of
chiral phosphine ligands such as (R)‐BINAP, (R,R)‐QuinoxP* and
(R,R)‐BenzP* also gave poor results (Table 2, entries 4 6). The nature of the
proton source was also determined to be important to the reactivity and
enantioselectivity observed during the transformation (Table 2, entries 7 and
8). For example, the use of i‐PrOH instead of MeOH resulted in a low yield
(28%) and enantioselectivity (53% ee) (Table 2, entry 7). Furthermore, when
the reaction was conducted without MeOH, the reaction was not completed
O
H
CuCl (2 mol %)ICyHCl (2 mol %)2 (1.0 equiv)
K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)toluene, rt, 1 hthen work up
1a
protection
H
B(pin)PGO
rac-3aR H
HO B(pin)
not isolated>99% conversion
isolated yield
Ph Ph
entry PG reaction conditions isolated yield (%)
1
2
3
4
5
6
7
8
Bn-
Bn-
Me-
PhCO-
PhCO-
PhCO-
Me2NCO-
Me3Si-
BnBr, NaH, THF
Benzyloxypyridinium salt, MgO
Me3OBF4, CH2Cl2PhCOOH, EDC, DMAP
(PhCO)2O, DMAP, CH2Cl2PhCOCl, pyridine, DMAP
Me2NCOCl, pyridine, CH2Cl2Me3SiCl, imidazole, CH2Cl2
26
33
28
22
20
17
<5
64
147
after longer reaction time (24 h) to afford a lower yield (34%) of the product
with a lower enantioselectivity (22% ee) (Table 2, entry 8). This
enantioselective borylation also proceeded with 1 mol % copper(I) catalyst
and showed high enantioselectivity (96% ee), while longer reaction time was
required for the completion of the reaction (Table 2, entry 9).
Next, the author proceeded to investigate the scope of enantioselective
borylation using various aldehydes (Table 3). The reaction of simple aliphatic
aldehydes proceeded well to give the desired products in sufficient yields
with high enantioselectivities (Table 3, entries 1 5). Pleasingly, the products
of the reactions involving α‐branched aliphatic aldehydes could be isolated
by flash column chromatography in good yields without the need for the
protection of the alcohol moiety (Table 3, entries 2 and 3). It is noteworthy
that this reaction exhibited good functional group compatibility, with
aliphatic aldehydes bearing acetal, ester, Boc‐protected amine, sulfonamide
and benzyl ether groups reacting smoothly to give the corresponding chiral
boronates with high enantioselectivities (Table 3, entries 6 10).
Unfortunately, however, pivalaldehyde did not react under the current
conditions (Table 3, entry 11). Several aromatic aldehydes were also
investigated (Table 3, entries 12 14). 16 Benzaldehyde proceeded through the
reaction with high enantioselectivity (90% ee) to give the desired product,
albeit in a low isolated yield (i.e., 66% yield by NMR, 34% isolated yield)
because of the poor stability of the product towards purification by column
chromatography over silica gel (Table 3, entry 12). The application of the
optimized conditions to the more sterically hindered 2‐methylbenzaldehyde
led to an improved chemical yield (66%), but the enantioselectivity was
decreased (65% ee) (Table 2, entry 13). 2‐Naphtaldehyde was also reacted
with high enantioselectivity (99% ee), but resulted in a low isolated yield
(22%) (Table 3, entry 14). Pleasingly, we found that the product derived from
2‐naphtaldehyde could be isolated in good yield by converting the
corresponding potassiumα‐hydroxylalkyltrifluoroborate using KHF2
(71%).9
148
Table 2. Reaction Optimization Study
1. CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %) alcohol (2.0 equiv) THF, 30 C, 6 h
2. BnMe2SiCl (1.0 equiv) imidazole (3.0 equiv) CH2Cl2, 3 h
1a
Ph H
(S)-3a
B(pin)BnMe2SiO
Ph H
OB B
O
O O
O+
2(1.0 equiv)
entry chiral ligand NMR yield (%)
1
2
3
4
5
6
7c
8d
9e
72
71
74
66
61
68
28
34
65
(R)-DTBM-SEGPHOS
(R)-DM-SEGPHOS
(R)-SEGPHOS
(R)-BINAP
(R,R)-QuinoxP*
(R,R)-BenzP*
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
(R)-DTBM-SEGPHOS
alcohol
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
i-PrOH
none
MeOH
ee (%)
96
32
24
69
69
60
53
22
96
aConditions: CuCl (0.025 mmol), ligand (0.025 mmol), 1a (0.5 mmol), bis(pinacolato)diboron (2) (0.5 mmol) and K(O-t-Bu) (0.05 mmol) in THF (1.0 mL). bThe ee values for 3a were determined by HPLC analysis. cThe reaction time was 15 h. dThe reaction time was 24 h. eThe reaction was carried out with 1 mol % copper(I) catalyst and the reaction time was 24 h.
P
P
Me tBu
tBu Me
(R,R)-BenzP*
N
N P
P
Me tBu
tBu Me
(R,R)-QuinoxP*
O
O
O
O
PPh2
PPh2
PPh2
PPh2
(R)-SEGPHOS (R)-BINAP
O
O
O
O
P
P
Me
Me
Me
Me
2
2
(R)-DM-SEGPHOS
O
O
O
O
P
P
tBu
OMe
tButBu
OMetBu
2
2
(R)-DTBM-SEGPHOS
149
Table 3. Substrate Scope
69 907
entry substrate product ee (%)c
51 961
yield (%)b
77 962
82 923
61 954
84 955
66 856
81 958
HH
O
1b (S)-3b
B(pin)Me3SiO
HH
O
1c (S)-3c
B(pin)HO
HH
O
1d (S)-3d
B(pin)HO
HH
O
1e (S)-3e
B(pin)Me3SiO
HH
O
1f (S)-3f
B(pin)Me3SiO
HO
O
HO
O
O
1g (S)-3g
B(pin)BnMe2SiO
H
BzO
H
BzO
O
1h (S)-3h
B(pin)BnMe2SiO
NBoc
H
NBoc
H
O
1i (S)-3i
B(pin)BnMe2SiO
NTs
H
NTs
H
O
1j (S)-3j
B(pin)Me3SiO
52 919
150
The author also tested the asymmetric borylation of chiral aldehyde
substrates to ensure the extent of substrate versus catalyst control (Scheme 3).
While reaction of (R)‐citronellal [(R)‐1p] led to diastereomeric mixtures (d.r.
52:48) using the ICy/CuCl achiral catalyst, excellent diastereoselectivities (d.r.
>95:5) were observed when chiral DTBM‐SEGPHOS ligand was used,
indicating complete catalyst control (Scheme 2a). Furthermore, employing
ICy as the ligand for the borylation of α chiral aldehyde ( R)‐1q resulted in a
moderate diastereomeric ratio (d.r. 30:70) while using the ligand (R)‐ and
(S)‐DTBM‐SEGPHOS provided high catalyst‐controlled stereoselectivities
(d.r. 89:11 and >95:5, respectively) (Scheme 2b).
H
BnO
H
BnO
O
1k (S)-3k
B(pin)Me3SiO
69 9510
O
H Ht-Bu t-Bu1l (S)-3l
B(pin)HOtrace 11
Ph H(S)-3m
Ph H 1m
O B(pin)MePh2SiO34 9012
o-Tol H (S)-3no-Tol H 1n
O B(pin)BnMe2SiO66 6513
2-naph H(S)-3o
2-naph H
O
1o
B(pin)MePh2SiO22 9914
aConditions: CuCl (0.025 mmol), ligand (0.025 mmol), 1 (0.5 mmol), bis(pinacolato)diboron(2) (0.5 mmol) and K(O-t-Bu) (0.05 mmol) in THF (1.0 mL). bIsolated yield. cThe ee values for 3 were determined by HPLC analysis after derivatization.
151
Scheme 3. Catalyst‐Controlled Asymmetric Borylation of Chiral Aldehyde
Substrates
To demonstrate utility of this protocol, we investigated the gram‐scale
synthesis of α‐alkoxyorganoboronate esters (Scheme 4). The borylation of 1a
was carried out on 4.0 mmol scale, affording the product (S)‐3a in good yield
with excellent enantioselectivity (67%, 96% ee).
Scheme 4. Gram‐Scale Synthesis of Enantioenriched Chiral
‐Alkoxyorganoboronate Esters
H
OMeCuCl / ligand (5 mol %)2 (1.0 equiv)K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)
solvent, 30 C, 6 hthen Me3SiClimidazole, 3 h
B(pin)
OSiMe3Me
B(pin)
OSiMe3Me
+
(R)-1p (R,S)-3p (R,R)-3p
ICyHCl (2 mol %), toluene: 63%, (R,S)-3p:(R,R)-3p = 52:48
CuCl / ligand (5 mol %)2 (1.0 equiv)K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)
solvent, 30 C, 18 hthen Me3SiClimidazole, 3 h (R,S)-3q
ICyHCl (2 mol %), toluene: 69%, (R,S)-3q:(R,R)-3q = 30:70
H
O
(R)-1qMe
TBSO
B(pin)
OSiMe3
Me
TBSO
(R,R)-3q
B(pin)
OSiMe3
Me
TBSO
+
(R)-DTBM-SEGPHOS, THF: 66%, (R,S)-3p:(R,R)-3p = >95:5(S)-DTBM-SEGPHOS, THF: 70%, (R,S)-3p:(R,R)-3p = 5:>95
(R)-DTBM-SEGPHOS, THF: 73%, (R,S)-3q:(R,R)-3q = 89:11(S)-DTBM-SEGPHOS, THF: 77%, (R,S)-3q:(R,R)-3q = 5:>95
a) Asymmetric borylation of aldehyde with -stereocenter
b) Asymmetric borylation of aldehyde with -stereocenter
1. CuCl (5 mol %) (R)-DTBM-SEGPHOS (5 mol %) K(O-t-Bu) (10 mol %) 2 (1.0 equiv), MeOH (2.0 equiv) THF, 30 C, 24 h
2. BnMe2SiCl, imidazole, 3 hPh
O
1a(4.0 mmol)
H
(S)-3a67%, 96% ee
(1.10 g)gram-scale preparation
keeping high enantioselectivity
Ph H
B(pin)BnMe2SiO
152
Enantioenriched α‐alkoxyorganoboronate esters could potentially be used
as building blocks in organic synthesis for the preparation of various
functionalized chiral compounds. With this in mind, the author conducted a
preliminary investigation of the stereospecific CC bond forming reactions of
the chiral boronate products using homologation methods (Scheme 4). The
borylation product ((S)‐3a) was subjected to a one‐carbon homologation
process where it was treated with a halomethyllithium reagent followed by
H2O2 oxidation to provide the desired alkylated diol product in a completely
stereospecific manner (Scheme 5).17 Furthermore, the chiral epoxide (R)‐6 was
successfully obtained using the same homologation strategy followed by a
bromination/deprotection sequence (Scheme 5).18 Aggarwal et al.19 recently
reported the enantiospecific coupling of optically active alkylboronates with
aryllithium compounds, and this novel method was applied to the chiral
boronate synthesized in the current study (Scheme 4b, eq. 8). The
cross‐coupling of (S)‐3e with benzofuran proceeded and the subsequent
deprotection of the silyl group afforded the arylated product (R)‐7 with
excellent stereospecificity.
Scheme 5. Stereospecific CC Bond Forming Reactions of Chiral
‐Alkoxyorganoboronate Esters
(S)-3a96% ee
ClCH2Brn-BuLi
THF78 C, 3 h
Ph H
BnMe2SiO
(R)-5
B(pin)
Ph H
HO OH
77%, 96% ee
Ph H
O
66%, 96% ee
H2O2
NaOH
THF, 1 h
(R)-6
H
Me3SiO B(pin) 1. benzofuran, n-BuLi THF, 78 C, 1 h
H
HOO
2. NBS, 78 C, 1 h then TBAF(S)-3e
95% ee52%, 95% ee
(R)-7
b) Stereospecific cross-coupling with heteroaromatic compound
a) Stereospecific alkylation / functionalization sequence
(R)-4
1. ArLi, 78 C2. NBS, 78 C
Ph H
BnMe2SiO Br TBAF
THF, rtAr = 3,5-(CF3)2C6H3
153
The author have proposed a possible reaction mechanism for the
current copper(I)‐catalyzed borylation of aldehydes, which is shown in
Figure 1.20 The reaction of CuCl with the ligand and K(O‐t‐Bu) would result
in the formation of copper(I) alkoxide A, which would initially react with
diboron 2 to afford the boryl copper(I) intermediate B. The coordination of
the aldehyde 1 to intermediate B would result in the formation of the
π‐complex C, which would undergo an insertion reaction to give the
borylated copper(I) alkoxide D. The protonation of D would proceed in the
presence of methanol to give the borylation product 3 as well as regenerating
the copper(I) alkoxide A.
Figure 1. Proposed Reaction Mechanism for Copper(I)‐Catalyzed
Enantioselective Borylation of Aldehydes
Conclusion
In summary, the author have developed, for the first time, enantioselective
nucleophilic borylation of aldehydes using a copper(I)/DTBM‐SEGPHOS
chiral complex catalyst to afford chiral ‐alkoxyorganoboronate esters with
excellent enantioselectivities. The newly synthesized chiral
α‐alkoxyorganoboronate esters could be transformed to functionalized chiral
alcohol derivatives using stereospecific CC bond forming reactions.
Recently, copper(I)‐catalyzed enantioselective 1,2‐silyl additions to C=O and
C=N double bonds using a silylboron reagent have been reported.20 The
author believes that these studies as well as the present work on the catalytic
Cu B(pin)P
P
CuB(pin)
P
P
O CH
R
O C
Cu
R
B(pin)P
P
O C
H
R
B(pin)
Cu ORP
P
P
P= (R)-DTBM-SEGPHOS
R = OMe or O-t-Bu
O CH
R
(pin)BB(pin)
MeOH
(pin)BOR
A
B
C
D3
coordination
protonation
-bondmethathesis
HH
insertion
1
2
154
enantioselective 1,2‐metal addition of carbonyl compounds will provide
attractive umpolung pathways for the synthesis of useful enantioenriched
functionalized alcohols. Further studies directed towards the elucidation of
the reaction mechanism20 and the development of methodologies for the
enantioselective borylation of other carbonyl compounds such as ketones as
well as imines are currently underway.
155
Experimental
General.
Materials were obtained from commercial suppliers and purified by
standard procedures unless otherwise noted. Solvents were also purchased
from commercial suppliers, degassed via three freeze‐pump‐thaw cycles, and
further dried over molecular sieves (MS 4A). NMR spectra were recorded on
JEOL JNM‐ECX400P and JNM‐ECS400 spectrometers (1H: 400 MHz and 13C:
100 MHz).Tetramethylsilane (1H) and CDCl3 (13C) were employed as external
standards, respectively. CuCl (ReagentPlus® grade, 224332‐25G, ≥99%) and
K(O‐t‐Bu) / THF (1.0 M, 328650‐50ML) were purchased from Sigma‐Aldrich
Co. and used as received. Tetrachloroethane was used as an internal standard
to determine NMR yields. GLC analyses were conducted with a Shimadzu
GC‐2014 or GC‐2025 equipped with ULBON HR‐1 glass capillary column
(Shinwa Chemical Industries) and a FID detector. HPLC analyses with chiral
stationary phase were carried out using a Hitachi LaChrome Elite HPLC
system with a L‐2400 UV detector. Elemental analyses and high‐resolution
mass spectra were recorded at the Center for Instrumental Analysis,
Hokkaido University.
Procedure for the Copper(I)‐Catalyzed Enantioselective Borylation of 1a
(Table 1).
Copper chloride (2.5 mg, 0.025 mmol) and bis(pinacolato)diboron (127.0 mg,
0.50 mmol), (R)‐DTBM‐SEGPHOS (29.5 mg, 0.025 mmol) were placed in an
oven‐dried reaction vial. After the vial was sealed with a screw cap
containing a teflon‐coated rubber septum, the vial was connected to a
vacuum/nitrogen manifold through a needle. It was evacuated and then
backfilled with nitrogen. This cycle was repeated three times. THF (1.0 mL)
and K(O‐t‐Bu)/THF (1.0 M, 0.05 mL, 0.05 mmol) were added in the vial
through the rubber septum. After 1a (67.4 mg, 0.50 mmol) was added to the
mixture at 30 °C, MeOH (40.5 μL, 1.0 mmol) was added dropwise. After the
reaction was complete, the reaction mixture was passed through a short silica
156
gel column eluting with Et2O. The crude mixture was placed in a reaction
vial and then diluted with CH2Cl2. Imidazole (102.1 mg, 1.5 mmol) was
added to the solution and then BnMe2SiCl (92.4 mg, 0.50 mmol) was added
dropwise. After stirred for 3 h, the mixture was passed through a short silica
gel column eluting with Et2O/CH2Cl2 (1:1). The crude material was purified
by flash column chromatography (SiO2, Et2O/hexane, typically 0:100–8:92) to
give the corresponding borylation product (S)‐3a as a colorless oil. The flash
column chromatography should be done within 5 min after the crude
mixture was applied on the silica gel surface; otherwise the products are
obtained in low yield. As for products containing polar functional groups,
their longer retention time in the column may have resulted in
decomposition of products, leading to a lower isolated yield.
The Choice of Silyl Protecting Group for Isolating the Borylation
Products.
We used various silyl protecting groups (Me3Si to BnMe2Si to Ph2MeSi) to
facilitate the isolation and the HPLC analysis. We chose the silyl protecting
group with two intentions in mind. One is to enable UV detection for
aldehydes without UV‐detectable functional group, by attaching a detectable
protecting group. The other is to ensure clean peak separation during HPLC
analysis. For example, for chiral organoboronate 3a, using the BnMe2Si group
enabled better peak separation in comparison to when it was protected using
other silyl groups.
157
The substrates for asymmetric borylation 1a1g and 1l1n were
purchased from commercial suppliers. The received aldehydes from the
suppliers were subjected to purification by distillation under reduced
pressure before use.
Preparation of 5‐oxopentyl benzoate (1h).22, 23
A solution of diol (7.4 mL, 70.0 mmol) in THF (18.0 mL) was added
dropwise to a suspension of NaH (60 wt.%, 480.0 mg, 12.0 mmol) in THF
(36.0 mL) at room temperature. Benzoyl chloride (1.20 mL, 10.0 mmol) was
then added to the mixture and the reaction mixture was stirred for 5 h. The
resulting suspension was diluted with diethyl ether and quenched by the
addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc
three times and dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (SiO2,
EtOAc/hexane, 3:97–20:80) to afford the mono‐protected product (1.624 g, 7.8
mmol, 78%) as a colorless oil.
A solution of dimethyl sulfoxide (DMSO) (425.0 μL, 6.0 mmol) in CH2Cl2
(2.5 mL) was added to a solution of oxalylchloride (308.7 μL, 3.6 mmol) in
CH2Cl2 (10.0 mL) at –78 °C. The mixture was stirred for 5 min at –78 °C and a
solution of diol (624.8 mg, 3.0 mmol) in CH2Cl2 (2.5 mL) was added dropwise.
After stirring for 15 min, Et3N (1.7 mL, 12.0 mmol) was added to the reaction
mixture within 5 min and then allowed to warm to 0 °C. Aqueous NaHCO3
was added to the reaction mixture after 30 min, the mixture was then
extracted with CH2Cl2 three times and dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash
HO BzO
1h
OHNaH (1.2 equiv)BzCl (1.0 equiv)
7.0 equiv
THF, 0 Crt
OH
DMSO (2.0 equiv)(COCl)2 (1.2 equiv)
Et3N (4.0 equiv)CH2Cl2, 78 Crt BzO
O
H
158
chromatography (SiO2, EtOAc/hexane, 0:100–10:90) to afford the
corresponding aldehyde 1h (532.1 mg, 2.6 mmol, 86%) as a colorless oil. 1H NMR (392 MHz, CDCl3, δ): 1.76–1.88 (m, 4H), 2.50–2.59 (m, 2H), 4.35 (t, J
= 6.2 Hz, 2H), 7.45 (t, J = 7.9 Hz, 2H), 7.57 (tt, J = 1.5, 7.6 Hz, 1H), 8.01–8.07 (m,
2H), 9.81 (t, J = 1.5 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): 18.8 (CH2), 28.2
(CH2), 43.4 (CH2), 64.5 (CH2), 128.5 (CH), 129.6 (CH), 130.3 (C), 133.0 (CH),
166.6 (C), 202.1 (CH). HRMS–ESI (m/z): [M+H]+ calcd for C12H15O3, 207.10157;
found, 207.10180.
Preparation of tert‐butyl 4‐formylpiperidine‐1‐carboxylate (1i).
The starting material was purchased from commercially suppliers. A
solution of DMSO (568.0 μL, 8.0 mmol) in CH2Cl2 (3.5 mL) was added to a
solution of oxalylchloride (411.6 μL, 8.0 mmol) in CH2Cl2 (13.0 mL) at –78 °C.
The mixture was stirred for 5 min at –78 °C and a solution of alcohol (861.2
mg, 4.0 mmol) in CH2Cl2 (3.5 mL) was added dropwise. After stirring for 15
min, Et3N (2.2 mL, 16.0 mmol) was added to the mixture within 5 min, and
then the reaction mixture was allowed to warm to 0 °C. Aqueous NaHCO3
was added to the mixture after 30 min and the mixture was extracted with
CH2Cl2 three times and dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography (SiO2,
EtOAc/hexane, 5:95–30:70) to afford the corresponding aldehyde 1i (725.1 mg,
3.4 mmol, 85%) as a white solid. 1H NMR (392 MHz, CDCl3, δ): 1.46 (s, 9H), 1.49–1.62 (m, 2H), 1.90 (br, d, J =
11.4 Hz, 2H), 2.42 (tt, J = 4.1, 10.7 Hz, 1H), 2.93 (t, J = 11.4 Hz, 2H), 3.99 (br, d, J
= 8.1 Hz, 2H), 9.67 (s, 1H). 13C NMR (99 MHz, CDCl3, δ): 24.5 (CH2), 27.8
(CH3), 42.5 (br, CH2), 47.2 (CH), 78.8 (C), 153.9 (C), 202.2 (CH). HRMS–EI
(m/z): [M]+ calcd for C11H19NO3, 213.13591; found, 213.13649.
NBoc
H
O
1i
NBoc
OH DMSO (2.0 equiv)(COCl)2 (1.2 equiv)
Et3N (4.0 equiv)CH2Cl2, 78 Crt
159
Preparation of N‐tosylpiperidine‐4‐carbaldehyde (1j).
The starting material was obtained from the corresponding amine through
the standard tosyl protection. A solution of the ethyl ester (7.785 g, 25.0
mmol) in Et2O (25.0 mL) was added dropwise to a slurry of LiAlH4 (1.423 g,
37.5 mmol) in Et2O (25.0 mL) at 0 °C. After stirred for 20 min, the reaction
mixture was quenched by addition of water and stirred until a white solid
was formed. The mixture was filtered and dried over MgSO4. The solvents
were removed by evaporation under reduced pressure. The residue was
purified by flash chromatography (SiO2, EtOAc/CH2Cl2, 0:100–5:95) to afford
the corresponding alcohol (6.061 g, 22.5 mmol, 90%) as a white solid.
A solution of DMSO (427.9 μL, 6.0 mmol) in CH2Cl2 (2.6 mL) was added
to a solution of oxalylchloride (308.8 μL, 3.6 mmol) in CH2Cl2 (10.0 mL) at –
78 °C. The mixture was stirred for 5 min at –78 °C and a solution of the
alcohol (808.0 g, 3.0 mmol) in CH2Cl2 (2.6 mL) was added dropwise. After
stirring for 15 min, Et3N (1.7 mL, 12.0 mmol) was added within 5 min and the
reaction mixture was allowed to warm to 0 °C. Aqueous NaHCO3 was then
added after 30 min and the mixture was extracted with CH2Cl2 three times
and dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2, EtOAc/hexane,
2:98–10:90) to afford the corresponding aldehyde 1j (649.6 mg, 2.4 mmol,
81%) as a white solid. 1H NMR (392 MHz, CDCl3, δ): 1.72–1.84 (m, 2H), 1.97 (q, J = 4.2 Hz, 1H), 2.01
(q, J = 4.0 Hz, 1H), 2.23 (dq, J = 4.8, 14.7 Hz, 1H), 2.44 (s, 3H), 2.56–2.66 (m,
2H), 3.52 (dt, J = 4.4, 12.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz,
2H), 9.60 (s, 1H). 13C NMR (99 MHz, CDCl3, δ): 21.4 (CH3), 24.6 (CH2), 45.0
NTs
H
O
1j
NTs
OH
DMSO (2.0 equiv)(COCl)2 (1.2 equiv)
Et3N (4.0 equiv)CH2Cl2, 78 Crt
NTs
O
OLiAlH4 (1.5 equiv)
Et2O, 0 C, 20 h
160
(CH2), 46.6 (CH), 127.5 (CH), 129.6 (CH), 132.8 (C), 143.6 (C), 202.3 (CH).
HRMS–EI (m/z): [M+H]+ calcd for C13H18NO3S, 268.10019; found, 268.10057.
Preparation of 5‐(benzyloxy)pentanal (1k).
A solution of diol (7.4 mL, 70.0 mmol) in THF (18.0 mL) was added to a
suspension of NaH (60 wt.%, 480.0 mg, 12.0 mmol) in THF (36.0 mL) at room
temperature. Benzyl bromide (1.2 mL, 10.0 mmol) was then added and the
reaction mixture was stirred for 5 h. The resulting suspension was diluted
with ether and quenched with saturated aqueous NH4Cl. The mixture was
extracted with EtOAc three times and dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash
chromatography (SiO2, EtOAc/hexane, 0:100–40:60) to afford the
mono‐protected product (1.789 g, 9.2 mmol, 92%) as a colorless oil.
A solution of DMSO (1.28 mL, 18.0 mmol) in CH2Cl2 (8.0 mL) was added to
a solution of oxalylchloride (926.2 μL, 10.8 mmol) in CH2Cl2 (32.0 mL) at –
78 °C. The mixture was stirred for 5 min at –78 °C and a solution of diol (1.75
g, 9.0 mmol) in CH2Cl2 (8.0 mL) was added dropwise. After stirring for 15
min, Et3N (5.0 mL, 36.0 mmol) was added within 5 min and the reaction
mixture was allowed to warm to 0 °C. Aqueous NaHCO3 was then added
after 30 min and the mixture was extracted with CH2Cl2 three times and
dried over MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2, EtOAc/hexane, 0:100–
10:90) to afford the corresponding aldehyde 1k (1.52 g, 7.9 mmol, 88%) as a
colorless oil. 1H NMR (392 MHz, CDCl3, δ): 1.57–1.80 (m, 4H), 2.46 (dt, J = 1.7, 7.3 Hz,
2H), 3.49 (t, J = 6.2 Hz, 2H), 4.50 (s, 2H), 7.26–7.38 (m, 5H), 9.76 (t, J = 1.8 Hz,
1H). 13C NMR (99 MHz, CDCl3, δ): 18.9 (CH2), 29.1 (CH2), 43.5 (CH2), 69.7
(CH2), 72.9 (CH2), 127.56 (CH), 127.62 (CH), 128.4 (CH), 138.4 (C), 202.5 (CH).
HO BnO
1k
OHNaH (1.2 equiv)BnBr (1.0 equiv)
7.0 equiv
THF, 0 Crt
OH
DMSO (2.0 equiv)(COCl)2 (1.2 equiv)
Et3N (4.0 equiv)CH2Cl2, 78 Crt BnO
O
H
161
HRMS–EI (m/z): [M]+ calcd for C12H16O2, 192.11503; found, 192.11410.
Preparation of (R)‐3‐[(tert‐butyldimethylsilyl)oxy]‐2‐methylpropanal
[(R)‐1q].24
TBS chloride (2.26 g, 15.0 mmol) was added to a cooled (0 ℃) solution of
methyl (R)‐ hydroxyisobutyrate (1.18 g, 10.0 mmol) and imidazole (2.04 g,
30.0 mmol) in dry DMF (15.0 mL) under nitrogen atmosphere. After stirring
for 2 h at room temperature, water was then added and the mixture was
extracted with CH2Cl2 three times and dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash
chromatography (SiO2, EtOAc/hexane, 0:100–10:90) to afford the
corresponding silyl ether (2.32 g, 10.0 mmol, >99%) as a colorless oil.
DIBAL‐H (30.0 mL, 30.0 mmol, 1.0 M hexane, 3.0 equiv) was added to a
cooled ( 78 ℃) solution of protected ester (2.32g, 10 mmol) in dry CH2Cl2
(40.0 mL) under nitrogen atmosphere. After stirring for 30 min, water and
small amount of aqueous NaOH (2.5 M) were added and the mixture was
filtered through Celite. The resultant reaction mixture was then dried over
MgSO4, filtered and concentrated under reduced pressure to afford the
corresponding diol (1.70 g, 8.3 mmol, 83%) as a colorless oil.
A solution of DMSO (1.14 mL, 16.0 mmol) in CH2Cl2 (7.0 mL) was added to
a solution of oxalyl chloride (827.0 μL, 9.6 mmol) in CH2Cl2 (25.0 mL) at –
78 °C. The mixture was stirred for 5 min at –78 °C and a solution of the
alcohol (1.64 g, 8.0 mmol) in CH2Cl2 (7.0 mL) was added dropwise. After
stirring for 15 min, Et3N (4.5 mL, 32.0 mmol) was added and the reaction
mixture was stirred for 1 h at –78 °C. Aqueous NaHCO3 was then added at
O
OMe
Me
TBSCl (1.5 equiv)imidazole (3.0 equiv)
DMF, 0 Crt, 1.5 h
DIBAH (3.0 equiv)
CH2Cl2, 78 C30 min
DMSO (2.0 equiv)(COCl)2 (1.2 equiv)
Et3N (4.0 equiv)CH2Cl2, 78 C, 1 h
TBSO H
Me
O
HO O
OMe
Me
TBSO
OH
Me
TBSO
(R)-1q
162
0 °C and the mixture was extracted with CH2Cl2 three times and dried over
MgSO4, filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography (SiO2, EtOAc/hexane, 0:100–10:90) to
afford the corresponding aldehyde (R)‐1q (1.02 g, 5.04 mmol, 63%) as a
colorless oil. 1H NMR (392 MHz, CDCl3, δ): 0.055 (s, 6H), 0.88 (s, 9H), 1.09 (d, J = 7.0 Hz,
3H), 2.49–2.58 (m, 1H), 3.81 (dd, J = 6.4, 10.5 Hz, 1H), 3.85 (dd, J = 5.3, 10.4 Hz,
1H), 9.74 (d, J = 1.5 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): –5.62 (CH3), –5.59
(CH3), 10.2 (CH3), 18.1 (C), 25.7 (CH3), 48.7 (CH), 63.4 (CH2), 204.5 (CH).
HRMS–EI (m/z): [M CH 3]+ calcd for C9H19O2Si, 187.11543; found, 187.11512.
[α]D23.4 –53.65 (c 1.0 in CHCl3).
Borylation Product Characterization
(S)‐Benzyldimethyl[3‐phenyl‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)
propoxy]silane [(S)‐3a].
1H NMR (392 MHz, CDCl3, δ): 0.070 (s, 3H), 0.085 (s, 3H), 1.26 (s, 6H), 1.27 (s,
6H), 1.80–1.97 (m, 2H), 2.19 (d, J = 14.3 Hz, 1H), 2.25 (d, J = 13.9 Hz, 1H), 2.57–
2.67 (m, 1H), 2.69–2.80 (m, 1H), 3.58 (dd, J = 5.5, 8.1 Hz, 1H), 7.04–7.10 (m,
2H), 7.14–7.31 (m, 8H). 13C NMR (99 MHz, CDCl3, δ): –2.14 (CH3), –2.00 (CH3),
24.5 (CH3), 25.0 (CH3), 26.9 (CH2), 32.9 (CH2), 36.3 (CH2), 83.9 (C), 124.0 (CH),
125.6 (CH), 128.1 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 139.5 (C), 142.5 (C).
HRMS–ESI (m/z): [M+Na]+ calcd for C24H35O3BNaSi, 432.23770; found,
432.23764. [α]D20.9 –1.50 (c 1.0 in CHCl3, 96% ee). Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min, 40 °C, S isomer: tR = 10.89 min., R
isomer: tR = 16.55 min.
(S)‐Trimethyl[3‐methyl‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)butox
y]silane [(S)‐3b].
Ph H
(S)-3a
BnMe2SiO B(pin)
H
Me3SiO B(pin)
(S)-3b
163
1H NMR (392 MHz, CDCl3, δ): 0.10 (s, 9H), 0.88 (d, J = 6.6 Hz, 3H), 0.91 (d, J
= 7.0 Hz, 3H), 1.25 (s, 6H), 1.26 (s, 6H), 1.54–1.62 (m, 2H), 1.72–1.84 (m, 1H),
3.54 (dd, J = 4.4, 10.6 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): –0.063 (CH3), 21.5
(CH3), 23.5 (CH3), 24.2 (CH), 24.5 (CH3), 24.9 (CH3), 42.9 (CH2), 58.5 (br, B–CH),
83.6 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C14H31O3BNaSi, 308.20640; found,
308.20645. [α]D19.4 +10.83 (c 0.9 in CHCl3, 96% ee). The ee value was
determined by HPLC analysis of the corresponding ester after homologation,
deprotection of silyl ether using TBAF and subsequent esterification with
p‐nitorobenzoyl chloride of the borylated product in comparison of the
racemic sample. Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 1/99, 0.5
mL/min, 40 °C, S isomer: tR = 13.93 min., R isomer: tR = 17.35 min.
(S)‐2‐Methyl‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)propan‐1‐ol
[(S)‐3c].
1H NMR (392 MHz, CDCl3, δ): 0.96 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.3 Hz, 3H),
1.28 (s, 12H), 1.84–1.97 (m, 1H), 3.38 (t, J = 4.0 Hz, 1H). 13C NMR (99 MHz,
CDCl3, δ): 18.5 (CH3), 19.3 (CH3), 24.7 (CH3), 24.8 (CH3), 32.2 (CH), 66.3 (br, B–
CH), 84.0 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C10H21O3BNa, 222.15123;
found, 222.15142. [α]D26.6 –8.43 (c 1.6 in CHCl3, 96% ee). The ee value was
determined by HPLC analysis of the corresponding ester after standard silyl
protection, homologation, followed by deprotection of silyl ether using TBAF
and subsequent esterification with p‐nitorobenzoyl chloride of the borylated
product in comparison of the racemic sample. Daicel CHIRALPAK® IC‐3,
2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S isomer: tR = 26.75 min., R isomer:
tR = 32.11 min.
(S)‐2‐Ethyl‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)butan‐1‐ol
[(S)‐3d].
H
HO B(pin)
(S)-3c
H
HO B(pin)
(S)-3d
164
1H NMR (392 MHz, CDCl3, δ): 0.90–0.95 (m, 6H) 1.28 (s, 12H), 1.31–1.50 (m,
5H), 3.66 (br, s, 1H). 13C NMR (99 MHz, CDCl3, δ): 12.0 (CH3), 12.2 (CH3), 23.3
(CH2), 23.6 (CH2), 24.7 (CH3), 24.8 (CH3), 45.7 (CH), 62.1 (br, B–CH), 84.1 (C).
HRMS–ESI (m/z): [M+Na]+ calcd for C12H25O3BNa, 250.18253; found,
250.18187. [α]D20.5 –5.75 (c 1.0 in CHCl3, 93% ee). The ee value was determined
by HPLC analysis of the corresponding ester after standard silyl protection,
homologation, followed by deprotection of silyl ether using TBAF and
subsequent esterification with p‐nitorobenzoyl chloride of the borylated
product in comparison of the racemic sample. Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S isomer: tR = 13.41 min., R isomer:
tR = 15.64 min.
(S)‐[Cyclohexyl(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methoxy]trimet
hylsilane [(S)‐3e].
1H NMR (392 MHz, CDCl3, δ): 0.086 (s, 9H), 0.95–1.25 (m, 4H), 1.26 (s, 6H),
1.27 (s, 6H), 1.47–1.83 (m, 7H), 3.23 (d, J = 7.0 Hz, 1H). 13C NMR (99 MHz,
CDCl3, δ): –0.14 (CH3), 24.5 (CH3), 24.9 (CH3), 26.2 (CH2), 26.3 (CH2), 26.5
(CH2), 29.7 (CH2), 29.8 (CH2), 41.8 (CH), 66.0 (br, B–CH), 83.5 (C). HRMS–ESI
(m/z): [M+Na]+ calcd for C16H33O3BNaSi, 334.22205; found, 334.22222. [α]D21.6
+3.72 (c 1.1 in CHCl3, 95% ee). The ee value was determined by HPLC
analysis of the corresponding ester after homologation, deprotection of silyl
ether using TBAF and subsequent esterification with p‐nitorobenzoyl
chloride of the borylated product in comparison of the racemic sample.
Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C, S
isomer: tR = 14.57 min., R isomer: tR = 16.16 min.
(S)‐[Cycloheptyl(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)methoxy]trime
thylsilane [(S)‐3f].
H
Me3SiO B(pin)
(S)-3e
H
Me3SiO B(pin)
(S)-3f
165
1H NMR (392 MHz, CDCl3, δ): 0.089 (s, 9H), 1.15–1.81 (m, 13H), 1.26 (s, 6H),
1.27 (s, 6H), 3.23 (d, J = 6.9 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): –0.034
(CH3), 24.5 (CH3), 24.9 (CH3), 26.7 (CH2), 26.8 (CH2), 28.51 (CH2), 28.53 (CH2),
30.5 (CH2), 31.3 (CH2), 43.3 (CH), 66.0 (br, B–CH), 83.5 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C17H35O3BNaSi, 348.23770; found, 348.23784. [α]D19.3 +6.81 (c
1.1 in CHCl3, 95% ee). The ee value was determined by HPLC analysis of the
corresponding ester after homologation, deprotection of silyl ether using
TBAF and subsequent esterification with p‐nitorobenzoyl chloride of the
borylated product in comparison of the racemic sample. Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min, 40 °C, S
isomer: tR = 23.75 min., R isomer: tR = 29.17 min.
(S)‐Benzyl[4‐(5,5‐dimethyl‐1,3‐dioxan‐2‐yl)‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐diox
aborolan‐2‐yl)butoxy]dimethylsilane [(S)‐3g].
1H NMR (392 MHz, CDCl3, δ): 0.057 (s, 3H), 0.065 (s, 3H), 0.71 (s, 3H), 1.18 (s,
3H), 1.26 (s, 6H), 1.27 (s, 6H), 1.38–1.70 (m, 6H), 2.17 (d, J = 14.3 Hz, 1H), 2.22
(d, J = 13.9 Hz, 1H), 3.41 (d, J = 10.6 Hz, 2H), 3.51 (dd, J = 5.3, 7.9 Hz, 1H), 3.59
(d, J = 11.4 Hz, 2H), 3.60 (s, 1H), 4.39 (t, J = 5.1 Hz, 1H), 7.02–7.09 (m, 3H),
7.16–7.23 (m, 2H). 13C NMR (99 MHz, CDCl3, δ): –2.23 (CH3), –2.15 (CH3), 16.4
(CH2), 20.9 (CH2), 21.8 (CH3), 23.0 (CH3), 24.5 (CH3), 24.9 (CH3), 26.8 (CH2),
30.1 (C), 33.9 (CH2), 34.7 (CH2), 61.0 (br, B–CH), 77.1 (CH2), 83.7 (C), 102.1
(CH), 123.9 (CH), 128.0 (CH), 128.3 (CH), 139.5 (C). HRMS–ESI (m/z): [M+Na]+
calcd for C25H43O5BNaSi, 484.29013; found, 484.29005. [α]D19.6 +25.50 (c 1.1 in
CHCl3, 85% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5
mL/min, 40 °C, S isomer: tR = 14.80 min., R isomer: tR = 19.29 min.
(S)‐5‐(4,4,5,5‐Tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐5‐[(trimethylsilyl)oxy]pe
ntyl benzoate [(S)‐3h].
H
BnMe2SiO B(pin)
O
O
(S)-3g
H
BzO
BnMe2SiO B(pin)
(S)-3h
166
1H NMR (392 MHz, CDCl3, δ): 0.010 (s, 9H), 1.24 (s, 6H), 1.25 (s, 6H), 1.43–
1.56 (m, 1H), 1.57–1.71 (m, 3H), 1.73–1.85 (m, 2H), 3.48–3.52 (m, 1H), 4.32 (t, J
= 6.8 Hz, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.52–7.57 (m, 1H), 8.01–8.06 (m, 2H). 13C
NMR (99 MHz, CDCl3, δ): –0.11 (CH3), 23.0 (CH2), 24.4 (CH3), 24.9 (CH3), 28.7
(CH2), 33.7 (CH2), 61.0 (br, B–CH), 65.0 (CH2), 83.7 (C), 128.2 (CH), 129.5 (CH),
130.5 (C), 132.7 (CH), 166.6 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C21H35O5BNaSi, 428.22753; found, 428.22745. [α]D22.0 +18.25 (c 1.0 in CHCl3,
90% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min,
40 °C, R isomer: tR = 13.67 min., S isomer: tR = 14.36 min.
tert‐Butyl
(S)‐4‐{[(benzyldimethylsilyl)oxy][4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐y
l]methyl}piperidine‐1‐carboxylate [(S)‐3i].
1H NMR (392 MHz, CDCl3, δ): 0.036 (s, 3H), 0.058 (s, 3H), 1.21–1.29 (m, 1H),
1.26 (s, 6H), 1.27 (s, 6H), 1.46 (s, 9H), 1.56 (d, J = 13.2 Hz, 1H), 1.61–1.72 (m,
3H), 2.16 (d, J = 13.9 Hz, 1H), 2.22 (d, J = 14.3 Hz, 1H), 2.65 (br, s, 2H), 3.31 (d,
J = 6.6 Hz, 1H), 4.11 (br, s, 2H), 7.02–7.09 (m, 3H), 7.19 (t, J = 7.9 Hz, 2H). 13C
NMR (99 MHz, CDCl3, δ): –2.34 (CH3), –2.07 (CH3), 24.6 (CH3), 25.0 (CH3), 26.8
(CH2), 28.4 (CH3), 28.6 (CH2), 28.7 (CH2), 40.4 (CH), 44.0 (br, N–CH2), 65.0 (br,
B–CH), 79.1 (C), 83.8 (C), 124.0 (CH), 128.1 (CH), 128.4 (CH), 139.3 (C), 154.8
(C). HRMS–ESI (m/z): [M+Na]+ calcd for C26H44O5NBNaSi, 511.30103; found,
511.30131. [α]D20.4 +19.45 (c 1.1 in CHCl3, 95% ee). Daicel CHIRALPAK® OZ‐3,
2‐PrOH/Hexane = 0.25/99.75, 0.5 mL/min, 40 °C, R isomer: tR = 59.12 min., S
isomer: tR = 60.72 min.
(S)‐4‐{[4,4,5,5‐Tetramethyl‐1,3,2‐dioxaborolan‐2‐yl][(trimethylsilyl)oxy]met
hyl}‐1‐tosylpiperidine [(S)‐3j].
1H NMR (392 MHz, CDCl3, δ): 0.060 (s, 9H), 1.23 (s, 6H), 1.24 (s, 6H), 1.39–
NBoc
H
BnMe2SiO B(pin)
(S)-3i
NTs
H
Me3SiO B(pin)
(S)-3j
167
1.51 (m, 3H), 1.60–1.68 (m, 1H), 1.73–1.82 (m, 1H), 2.13–2.26 (m, 2H), 2.43 (s,
3H), 3.23 (d, J = 5.1 Hz, 1H), 3.77–3.87 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.64 (d,
J = 8.4, 2H). 13C NMR (99 MHz, CDCl3, δ): –0.21 (CH3), 21.4 (CH3), 24.5 (CH3),
24.9 (CH3), 28.0 (CH2), 28.2 (CH2), 39.4 (CH), 46.3 (CH), 46.5 (CH), 64.3 (br, B–
CH), 83.8 (C), 127.6 (CH), 129.5 (CH), 133.1 (C), 143.2 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C22H38O5NBNaSSi, 489.22615; found, 489.22590. [α]D20.3
+34.96 (c 1.5 in CHCl3, 92% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane
= 1/99, 0.5 mL/min, 40 °C, S isomer: tR = 21.72 min., R isomer: tR = 23.96 min.
(S)‐{[5‐(Benzyloxy)‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pentyl]ox
y}trimethylsilane [(S)‐3k].
1H NMR (392 MHz, CDCl3, δ): 0.094 (s, 9H), 1.24 (s, 6H), 1.25 (s, 6H), 1.33–
1.69 (m, 6H), 3.43–3.51 (m, 3H), 4.49 (s, 2H), 7.24–7.35 (m, 5H). 13C NMR (99
MHz, CDCl3, δ): –0.091 (CH3), 23.1 (CH2), 24.5 (CH3), 24.9 (CH3), 29.7 (CH2),
33.9 (CH2), 61.0 (br, B–CH), 70.4 (CH2), 72.8 (CH2), 83.6 (C), 127.4 (CH), 127.5
(CH), 128.3 (CH), 138.7 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C21H37O4BNaSi, 414.24827; found, 414.24834. [α]D19.3 +4.00 (c 1.0 in CHCl3, 95%
ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.1/99.9, 0.5 mL/min,
40 °C, R isomer: tR = 19.12 min., S isomer: tR = 20.00 min.
(S)‐Methyldiphenyl[phenyl(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)met
hoxy]silane [(S)‐3m].
1H NMR (392 MHz, CDCl3, δ): 0.61 (s, 3H), 1.12 (s, 12H), 4.76 (s, 1H), 7.18 (t,
J = 7.5 Hz, 1H), 7.23–7.43 (m, 10H), 7.55–7.65 (m, 4H). 13C NMR (99 MHz,
CDCl3, δ): –2.49 (CH3), 24.3 (CH3), 24.6 (CH3), 64.3 (br, B–CH), 84.0 (C), 125.7
(CH), 126.2 (CH), 127.66 (CH), 127.69 (CH), 128.1 (CH), 129.6 (CH), 134.5 (CH),
134.6 (CH), 136.2 (C), 136.3 (C), 141.8 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C26H31O3BNaSi, 452.20640; found, 452.20649. [α]D26.5 –10.00 (c 1.4 in CHCl3,
90% ee). Daicel CHIRALPAK® OZ‐3, 2‐PrOH/Hexane = 0.1/99.9, 0.5 mL/min,
H
BnO
Me3SiO B(pin)
(S)-3k
Ph H
(S)-3m
B(pin)MePh2SiO
168
40 °C, R isomer: tR = 11.03 min., S isomer: tR = 11.64 min.
(S)‐Benzyldimethyl[(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)(o‐tolyl)me
thoxy]silane [(S)‐3n].
1H NMR (392 MHz, CDCl3, δ): 0.021 (s, 3H), 0.039 (s, 3H), 1.18 (s, 6H), 1.20 (s,
6H), 2.15 (d, J = 13.9 Hz, 1H), 2.20 (d, J = 13.9 Hz, 1H), 2.28 (s, 3H), 4.71 (s, 1H),
6.98–7.21 (m, 8H), 7.46 (d, J = 7.7 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ): –2.26
(CH3), –1.93 (CH3), 19.4 (CH3), 24.4 (CH3), 24.6 (CH3), 27.0 (CH2), 62.3 (br, B–
CH), 83.8 (C), 123.9 (CH), 125.8 (CH), 126.1 (CH), 126.6 (CH), 128.1 (CH), 128.3
(CH), 129.8 (CH), 134.1 (C), 139.3 (C), 140.5 (C). HRMS–ESI (m/z): [M+Na]+
calcd for C23H33O3BNaSi, 418.22205; found, 418.22239. [α]D26.5 –16.44 (c 0.9 in
CHCl3, 65% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5
mL/min, 40 °C, R isomer: tR = 11.27 min., S isomer: tR = 12.05 min.
(S)‐Methyl[naphthalen‐2‐yl(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)met
hoxy]diphenylsilane [(S)‐3o].
(S)‐3o contained inseparable some impurities. 1H NMR (392 MHz, CDCl3, δ): 0.64 (s, 3H), 1.10 (s, 6H), 1.12 (s, 6H), 4.91 (s,
1H), 7.28–7.49 (m, 9H), 7.56–7.67 (m, 4H), 7.74–7.84 (m, 4H). 13C NMR (99
MHz, CDCl3, δ): –2.46 (CH3), 24.3 (CH3), 24.6 (CH3), 65.0 (br, B–CH), 84.0 (C),
123.9 (CH), 124.5 (CH), 125.1 (CH), 125.7 (CH), 127.5 (CH), 127.6 (CH), 127.68
(CH), 127.71 (CH), 127.9 (CH), 129.7 (CH), 132.3 (C), 133.5 (C), 134.6 (CH)
136.1 (C), 136.2 (C), 139.5 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C30H33O3BNaSi, 502.22205; found, 502.22264. [α]D23.5 –53.15 (c 1.0 in CHCl3,
99% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.1/99.9, 0.5 mL/min,
40 °C, R isomer: tR = 17.21 min., S isomer: tR = 18.41 min.
o-Tol H
(S)-3n
B(pin)BnMe2SiO
2-naph H
(S)-3o
B(pin)MePh2SiO
169
{[(1S,3R)‐3,7‐Dimethyl‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)oct‐6‐e
n‐1‐yl]oxy}trimethylsilane [(R,S)‐3p].
1H NMR (392 MHz, CDCl3, δ): 0.098 (s, 9H), 0.86 (d, J = 6.6 Hz, 3H), 1.15–
1.21 (m, 1H), 1.25 (s, 6H), 1.26 (s, 6H), 1.26–1.36 (m, 1H), 1.59 (s, 3H), 1.63–
1.71 (m, 3H), 1.67 (s, 3H), 1.97 (q, J = 7.8 Hz, 2H), 3.56 (dd, J = 4.0, 10.6 Hz, 1H),
5.10 (m, 1H). 13C NMR (99 MHz, CDCl3, δ): –0.053 (CH3), 17.6 (CH3), 18.7
(CH3), 24.5 (CH3), 24.9 (CH3), 25.56 (CH2), 25.64 (CH3), 28.6 (CH), 37.9 (CH2),
41.1 (CH2), 58.5 (br, B–CH), 83.6 (C), 125.0 (CH), 130.8 (C). HRMS–EI (m/z):
[M]+ calcd for C19H39O3BSi, 354.27615; found, 354.27559. [α]D25.5 +26.3 (c 1.0 in
CHCl3).
{[(1R,3R)‐3,7‐Dimethyl‐1‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)oct‐6‐
en‐1‐yl]oxy}trimethylsilane [(R,R)‐3p].
1H NMR (392 MHz, CDCl3, δ): 0.010 (s, 9H), 0.91 (d, J = 6.9 Hz, 3H), 1.01–
1.11 (m, 1H), 1.24 (s, 6H), 1.25 (s, 6H), 1.36–1.45 (m, 1H), 1.48 (t, J = 7.1 Hz,
2H), 1.56–1.59 (m, 1H), 1.59 (s, 3H), 1.67 (s, 3H), 1.88–2.06 (m, 2H), 3.56 (t, J =
7.7 Hz, 1H), 5.10 (m, 1H). 13C NMR (99 MHz, CDCl3, δ): –0.072 (CH3), 17.5
(CH3), 20.3 (CH3), 24.5 (CH3), 24.8 (CH3), 25.4 (CH2), 25.6 (CH3), 28.9 (CH), 36.4
(CH2), 41.6 (CH2), 58.5 (br, B–CH), 83.5 (C), 124.9 (CH), 130.8 (C). HRMS–EI
(m/z): [M]+ calcd for C19H39O3BSi, 354.27615; found, 354.27550. [α]D25.3 –22.90 (c
1.0 in CHCl3).
(4S,5R)‐2,2,5,8,8,9,9‐Heptamethyl‐4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐
2‐yl)‐3,7‐dioxa‐2,8‐disiladecane [(R,S)‐3q].
B(pin)
OSiMe3Me
(R,S)-3p
B(pin)
OSiMe3Me
(R,R)-3p
170
1H NMR (392 MHz, CDCl3, δ): 0.032 (s, 6H), 0.093 (s, 9H), 0.89 (s, 9H), 0.90
(d, J = 7.0 Hz, 3H), 1.26 (s, 6H), 1.27 (s, 6H), 1.83 1.92 (m, 1H), 3.41 (d, J = 7.7
Hz, 1H), 3.50 (dd, J = 7.1, 10.1 Hz, 1H), 3.64 (dd, J = 4.4, 9.9 Hz, 1H). 13C NMR
(99 MHz, CDCl3, δ): –5.40 (CH3), –5.31 (CH3), 0.053 ( CH3), 13.8 (CH3), 18.3
(C), 24.6 (CH3), 25.0 (CH3), 26.0 (CH3), 39.9 (CH), 62.0 (br, B–CH), 64.8 (CH2),
83.6 (C). HRMS–EI (m/z): [M CH 3]+ calcd for C18H40O4BSi2, 387.25582; found,
387.25516. [α]D24.9 +12.63 (c 1.2 in CHCl3).
(4R,5R)‐2,2,5,8,8,9,9‐Heptamethyl‐4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐
2‐yl)‐3,7‐dioxa‐2,8‐disiladecane [(R,R)‐3q].
1H NMR (392 MHz, CDCl3, δ): 0.034 (s, 3H), 0.037 (s, 3H), 0.089 (s, 9H), 0.89
(s, 9H), 0.92 (d, J = 7.3 Hz, 3H), 1.25 (s, 6H), 1.27 (s, 6H), 1.77 1.87 (m, 1H),
3.34 (dd, J = 7.7, 9.9 Hz, 1H), 3.60 3.66 (m, 2H). 13C NMR (99 MHz, CDCl3, δ):
–5.32 (CH3), 0.072 ( CH3), 13.1 (CH3), 18.3 (C), 24.4 (CH3), 25.1 (CH3), 26.0
(CH3), 39.9 (CH), 65.2 (CH2), 83.6 (C). HRMS–EI (m/z): [M CH 3]+ calcd for
C18H40O4BSi2, 387.25582; found, 387.25483. [α]D24.6 –6.32 (c 1.1 in CHCl3).
Borylation Product Functionalization Procedure
Procedure for the Synthesis of Chiral Diol (R)‐5 through the One‐Carbon
Homologation Following Oxidation of (S)‐3a.
The one‐carbon homologation was performed according to the literature
procedure.25 In an oven‐dried reaction vial, (S)‐3a (82.1 mg, 0.20 mmol) and
bromochloromethane (51.8 mg, 0.40 mmol) were dissolved in dry THF (2.5
mL) in nitrogen atmosphere. After the mixture was cooled to –78 °C, n‐BuLi
in hexane (1.55 M, 193.5 μL, 0.30 mmol) was added dropwise. The mixture
was stirred at –78 °C for 10 min, and then stirred at room temperature for 2 h.
The reaction mixture was quenched by the addition of aqueous NH4Cl,
(R,S)-3q
B(pin)
OSiMe3
Me
TBSO
(R,R)-3q
B(pin)
OSiMe3
Me
TBSO
171
extracted three times with Et2O, dried over MgSO4, and filtered. The
resulting product 4 was used in the next reaction without further
purification.
The boronate 4 was dissolved in THF (1.0 mL) and NaOH aq. (3.0 M, 1.0
mL), and the reaction mixture was cooled to 0 °C. Into the mixture, H2O2 aq.
(30%, 0.50 mL) was then added dropwise, and the resultant mixture was
stirred at 0 °C for 1 h. The reaction was quenched by the addition of aqueous
Na2S2O3, extracted three times with EtOAc, dried over MgSO4, and filtered.
The crude material was purified by flash column chromatography (SiO2,
EtOAc/hexane, 30:70–70:30) to give the corresponding diol (R)‐5 (25.6 mg,
0.15 mmol, 77%) as a colorless oil.
(R)‐4‐Phenylbutane‐1,2‐diol [(R)‐5].
1H NMR (392 MHz, CDCl3, δ): 1.68–1.83 (m, 2H), 2.19 (br, s, 1H), 2.39 (br, s,
1H), 2.65–2.73 (m, 1H), 2.77–2.85 (m, 1H), 3.46 (dd, J = 7.9, 11.2 Hz, 1H), 3.65
(dd, J = 2.6, 11.4 Hz, 1H), 3.69–3.78 (m, 1H), 7.17–7.32 (m, 5H). 13C NMR (99
MHz, CDCl3, δ): 31.7 (CH2), 34.6 (CH2), 66.7 (CH2), 71.5 (CH), 125.9 (CH),
128.35 (CH), 128.40 (CH), 141.6 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C10H14O2Na, 189.08890; found, 189.08892. [α]D19.3 +7.42 (c 1.0 in CHCl3, 96% ee).
Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 10/90, 0.5 mL/min, 40 °C, R
isomer: tR = 26.85 min., S isomer: tR = 35.33 min.
The absolute configuration of borylation product (S)‐3a was determined by
comparison of the optical rotation of the diol (R)‐5 and the literature value
for (S)‐5 [[α]D20 16.24 ( c 1.1 in CHCl3)].26
Procedure for the Synthesis of Chiral Epoxide (R)‐6 through the
One‐Carbon Homologation Following Bromination/Deprotection
Sequence of (S)‐3a.
The one‐carbon homologation was performed according to the procedure
described above. The sequential bromination was performed according to the
literature procedure with slight modification.27 n‐BuLi in hexane (1.55 M,
150.0 μL, 0.24 mmol) was added to a solution of
1‐bromo‐3,5‐bis(trifluoromethyl)benzene (42.0 μL, 0.24 mmol) in THF (2.0
(R)-5Ph H
HO OH
172
mL) at –78 °C. The mixture was stirred for 1 h at –78 °C before a solution of
boronate 4 (0.20 mmol) in THF (1.0 mL) was added dropwise. The reaction
mixture was stirred for 30 min at –78 °C to give the ate‐complex solution. A
solution of N‐bromosuccinimide (NBS) (42.8 mg, 0.24 mmol) in THF (2.0 mL)
was then added dropwise, and the mixture was stirred for 1 h at room
temperature. The reaction was quenched by the addition of aqueous Na2S2O3.
The mixture was then extracted three times with Et2O, dried over MgSO4,
and filtered. The obtained crude halohydrin was used in next step without
further purification.
Tetrabutylammonium fluoride (TBAF) in THF (1.0 M, 400.0 μL, 0.40 mmol)
was added to a solution of the halohydrin in THF (1.0 mL) at room
temperature. After stirred for 2 h, the mixture was passed through a short
silica gel column eluting with Et2O. The crude material was purified by flash
column chromatography (SiO2, Et2O/Hex, 0:100–5:95) to give the desired
chiral epoxide (R)‐6 as a colorless oil (19.6 mg, 0.13 mmol, 66%).
(R)‐2‐Phenethyloxirane [(R)‐6].
1H NMR (392 MHz, CDCl3, δ): 1.77–1.94 (m, 2H), 2.47 (dd, J = 2.8, 5.0 Hz,
1H), 2.70–2.88 (m, 3H), 2.92–2.99 (m, 1H), 7.16–7.34 (m, 5H). 13C NMR (99
MHz, CDCl3, δ): 32.2 (CH2), 34.3 (CH2), 47.2 (CH2), 51.8 (CH), 126.0 (CH),
128.3 (CH), 128.4 (CH), 141.2 (C). HRMS–ESI (m/z): [M]+ calcd for C10H12O,
148.08881; found, 148.08932. [α]D20.3 +2.50 (c 1.8 in CHCl3, 96% ee). Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min, 40 °C, R
isomer: tR = 20.36 min., S isomer: tR = 28.00 min.
Procedure for the Synthesis of Arylated Product (R)‐7 through the
Stereospecific Cross‐Coupling of (S)‐3h with Benzofuran.
The stereospecific cross‐coupling was performed according to the
literature procedure.28 A solution of benzofuran (28.3 mg, 0.24 mmol) in THF
(0.80 mL) was cooled to –78 °C and treated with n‐BuLi in hexane (1.55 M,
155.0 μL 0.24 mmol). The reaction mixture was warmed to room temperature
and stirred for 1 h. The mixture was then cooled to –78 °C and the boronate
(S)‐3h (65.3 mg, 0.20 mmol) was added as a solution in THF (0.40 mL) and
Ph H
O
(R)-6
173
the reaction stirred at the same temperature for 1 h. A solution of NBS (42.7
mg, 0.24 mmol) in THF (0.80 mL) was then added dropwise to the mixture.
After 1 h at –78 °C, Na2S2O3 aq. was added and the reaction mixture was
allowed to warm to room temperature. The mixture was extracted three
times with Et2O, dried over MgSO4, and filtered. The resulting crude product
was used in the next reaction without further purification. The crude
material was dissolved in THF (1.0 mL) and a THF solution of TBAF (1.0 M,
0.40 mL) was added to the mixture. After stirred for 2 h, the mixture was
passed through a short silica gel column eluting with EtOAc. The crude
material was purified by flash column chromatography (SiO2, EtOAc/hexane,
2:98–15:85) to give the arylated product (R)‐7 (25.4 mg, 0.10 mmol, 52%) as a
colorless oil.
(R)‐Benzofuran‐2‐yl(cycloheptyl)methanol [(R)‐7].
1H NMR (392 MHz, CDCl3, δ): 1.19–1.76 (m, 10H), 1.84–1.93 (m, 1H), 1.99 (t,
J = 5.1 Hz, 1H), 2.03–2.14 (m, 1H), 4.62 (t, J = 6.0 Hz, 1H), 6.60 (s, 1H), 7.16–
7.28 (m, 2H), 7.41–7.47 (m, 1H), 7.50–7.55 (m, 1H). 13C NMR (99 MHz, CDCl3,
δ): 26.6 (CH2), 26.7 (CH2), 28.3 (CH2), 28.5 (CH2), 29.1 (CH2), 44.1 (CH), 73.3
(CH), 103.3 (CH), 111.2 (CH), 120.9 (CH), 122.7 (CH), 123.9 (CH), 128.1 (C),
154.6 (C), 159.0 (C). HRMS–EI (m/z): [M]+ calcd for C16H20O2, 244.14633; found,
244.14537. [α]D20.9 +23.62 (c 0.8 in CHCl3, 95% ee). Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 3/97, 0.5 mL/min, 40 °C, R isomer: tR = 25.68 min., S isomer:
tR = 28.92 min.
H
HOO
(R)-7
174
References and Notes
(1) (a) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2 nd revised ed.; Hall, D. G., Ed.; Wiley‐VCH:
Weinheim, 2011. (b) Mlynarski, S, N.; Schuster, C. H.; Morken, J. P. Nature
2014, 505, 386. (c) Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.;
Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014,
513, 183.
(2) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426. (b)
Crudeen, C.; Hleba, Y.; Chen, A. J. Am. Chem. Soc. 2004, 126, 9200.
(3) The early examples of copper(I)‐catalyzed borylation reaction, see: (a) Ito,
H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821.
(b) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982.
(4) The selected examples of copper(I)‐catalyzed enantioselective borylation
reaction, see: (a) Lee, J.‐E.; Lee, J.‐E.; Yun, J.; Yun, J. Angew. Chem., Int. Ed.
2008, 47, 145. (b) Lillo, V.; Prieto, A.; Bonet, A.; Diaz‐Requejo, M. M.; Ramirez,
J.; Perez, P. J.; Fernandez, E. Organometallics 2009, 28, 659. (c) Lee, Y.;
Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160. (d) Noh, D.; Chea, H.; Ju, J.;
Yun, J. Angew. Chem. Int. Ed. 2009, 48, 6062. (e) Chen, I.‐H.; Yin, L.; Itano, W.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 11664. (f) Moure, A. L.;
Gómez Arrayás, R.; Carretero, J. C. Chem Commun. 2011, 47, 6701. (g) Lee, J. C.
H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894. (k) X. Feng, H. Jeon, J.
Yun, Angew. Chem. Int. Ed. 2013, 52, 3989.
(5) For Ito and Sawamura’s selected studies on copper(I)‐catalyzed
enantioselective borylation reactions, see: (a) Ito, H.; Ito, S.; Sasaki, Y.;
Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (b) Sasaki, Y.;
Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226. (c) Ito, H.;
Kunii, S.; Sawamura, M. Nat. Chem. 2010, 2, 972.
(6) Asymmetric copper(I)‐catalyzed borylations of C=N bonds, see: (a) Beene,
M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910. (b) Wen, K.;
Wang, H.; Chen, J.; Zhang, H.; Cui, X.; Wei, C.; Fan, E.; Sun, Z. J. Org. Chem.
2013, 78, 3405. (c) Zhang, S.‐S.; Zhao, Y.‐S.; Tian, P.; Lin, G.‐Q. Synlett 2013, 24,
437.
(7) Sole, C.; Gulyas H.; Fernandez, E. Chem. Commun. 2012, 48, 3769.
175
(8) (a) He, A.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 6586. (b) Goli, M.; He,
A.; Falck, J. R. Org. Lett. 2011, 13, 344.
(9) Molander, G. A.; Wisniewski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
(10) For a review of Matteson homologation chemistry, see: Matteson, D. S.
Tetrahedron 1998, 54, 10555.
(11) Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113.
(12) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128, 11036.
(13) Mclntosh, M. L.; Moore, C. M.; Clark, T. B. Org. Lett. 2010, 12, 1996.
(14) Tummatom, J.; Albiniak, P. A.; Dudley, G. B. J. Org. Chem. 2007, 72,
8962.
(15) Various silyl protecting groups were used to facilitate HPLC detection
and did not influence the isolability and the yields. The details have been
discussed in SI.
(16) Borylations of p‐MeO‐ and p‐CF3‐substituted benzaldehydes were also
conducted, but resulted in decomposing the products during purification by
silica gel column.
(17) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(18) Larouche‐Gauthier, R.; Elfold, T. G.; Aggarwal, V. K. J. Am. Chem. Soc.
2011, 133, 16794.
(19) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nat.
Chem. 2014, 6, 584.
(20) The theoretical investigation for the borylation of a C=O double bond
using copper(I)/NHC complex catalyst, see: Zhao, H.; Dang, L.; Marder, T. B.;
Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
(21) (a) Vyas, D. J.; Frohlich, R.; Oestreich, M. Org. Lett. 2011. 13. 2094. (b)
Kleeberg, C.; Feldmann, E.; Hartmann, E.; Vyas, D.; Oestreich, M. Chem. Eur.
J. 2011, 17, 13538. (c) Cirriez, V.; Rasson, C.; Hermant, T.; Petrignet, J.;
Álvarez, J. D.; Robeyns, K.; Oestreich, M. Angew. Chem., Int. Ed. 2013, 52, 1785.
(d) Hensel, A.; Nagura, K.; Delvos, L. B.; Oestreich, M. Angew. Chem., Int.
Ed. 2014, 53, 4964.
(22) Liniger, M.; Neuhaus, C.; Hofmann, T.; Fransioli‐Ignazio, L.; Jordi, M.;
Drueckes, P.; Trappe, J.; Fabbro, D.; Altmann, K. ACS Med. Chem. Lett. 2011, 2,
22.
(23) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465.
(24) Rink, C.; Navickas, V.; Maier, M. E. Org. Lett. 2011, 13, 2334.
(25) Sadhu, K.M.; Matteson, D. S. Organometallics. 1985, 4, 1687.
176
(26) Kliman, L. T.; Mlynarski, S. N.; Morken, J. P. J. Am. Chem. Soc. 2009, 131,
13210.
(27) Larouche‐Gauthier, R.; Elfold, T. G.; Aggarwal, V. K. J. Am. Chem. Soc.
2011, 133, 16794.
(28) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nat.
Chem. 2014, 6, 584.
177
Chapter 5.
Computational Insight into the Enantioselective
Borylation of Aldehydes Catalyzed by Chiral
Bisphosphine Copper(I) Complexes
178
Abstract
Density functional theory calculations were performed to validate the
proposed reaction mechanism for the enantioselective nucleophilic
borylation of a polarized C=O double bond in the presence of
diphosphine/borylcopper(I) complexes. Consequently, the author
successfully elucidated the origin for the regioselectivity and the mechanism
for the enantioselectivity of the reaction. The author also obtained theoretical
explanations for the fact that the presence of a proton source gave a higher
reactivity and a better enantioselectivity in the borylation reaction of
aldehydes with a copper(I)/(R)‐DTBM‐SEGPHOS complex catalyst. This
study is particularly valuable toward the development and design of novel
enantioselective borylation reactions with polarized carbon‐heteroatom
double bonds.
Introduction
Organoboron compounds have attracted significant attention due to their
broad range of synthetic and medicinal applications.1 Synthetic strategies
that utilize metal‐catalyzed borylation strategies have recently made
significant contributions toward the efficient preparation of various
organoboron compounds. Copper(I)‐catalyzed reactions are a particularly
powerful tool for the umpolung nucleophilic addition of a boryl group to
various electrophiles such as aldehydes.2‐6 The study that originally
pioneered the catalytic borylation of a polarized C=O double bond was
reported by Sadighi et al. in 2006. They discovered that an N‐heterocyclic
carbine(NHC)/copper(I) complex could catalyze the diboration of both
aliphatic and aromatic aldehydes 1 with a diboron reagent 2 (Scheme 1a).3
Molander et al. later reported on the copper(I)‐catalyzed monoborylation of
aldehydes with the addition of methanol as a proton source to give
‐hydroxyalkylboron compounds.4 In a study on the diboration of
aldehydes, it was discovered that the borylation of mesitaldehyde (1a) in the
presence of a stoichiometric amount of (IPr)Cu‐B(pin) [IPr =
1,3,‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene] 4 gave a compound,
179
(IPr)Cu‐CHAr[OB(pin)] (Ar = 2,4,6‐Me3C6H2) 5 that contained a Cu C σ
bond (Scheme 1b).3 This result was particularly intriguing because it
suggested that the B(pin) ligand most likely acted as a boryl nucleophile to
form the C B and Cu O bonds. Lin and Marder et al. then reported on a
theoretical study regarding the mechanism of aldehyde insertion chemistry
using density functional theory (DFT) calculations (Scheme 1c).5 They
demonstrated that diboration proceeds through the 1,2‐addition of the
borylcopper(I) complex to a C=O double bond to form intermediate 6 with a
Cu O C B linkage. T his is followed by a metathesis reaction with an
additional diboron compound 3 (path A, Scheme 1c). In the absence of the
additional diboron reagent, the isomerization of the insertion intermediate 6
generates a more thermodynamically stable isomer 7. This compound
contains a Cu C O B linkage due to a boryl migration (path B, Scheme
1c).
Scheme 1. (a) The First Catalytic Borylation of Aldehydes. (b) Stoichiometric
Borylation of Mesitaldehyde. (c) Proposed Mechanism based on DFT
calculation.
180
The author reported on the copper(I)‐catalyzed enantioselective
nucleophilic borylation of aliphatic and aromatic aldehydes (Scheme 2).6
Aliphatic aldehyde 1b was reacted with bis(pinacolato)diboron (2) (1.0
equiv) in the presence of CuCl/(R)‐DTBM‐SEGPHOS (5 mol %), K(O‐t‐Bu)
(10 mol %), and a proton source, MeOH (2.0 equiv) in THF at 30 °C to afford
the desired product (S)‐8 in a relatively high yield (72%). This reaction also
gave an excellent enantioselectivity (96% ee) after the crude
‐hydroxyalkylboronate was protected by a silyl group. It was not possible
to obtain an enantioenriched product from the nucleophilic borylation of a
polarized C=O double bond prior to this discovery.7‐10
Scheme 2. Enantioselective Borylation of Aldehydes in the presence of Chiral
DTBM‐SEGPHOS/Copper(I) Complex Catalysis
R H
O
R = Alkyl, Aryl
cat. Cu(I) / ICy
benzene, rtB B
O
O O
O+
R B(pin)
O
a) Copper(I)-catalyzed diborylation reported by Sadighi (2006)
b) Stoichiometric reaction reported by Sadighi (2006)
1 2racemic
H
OIPrCuB(pin) (4)
pentane, 1 hCuL
OB(pin)
B(pin)
O
not observed
c) Mechanism proposed by Lin and Marder (2008)
R B(pin)
OCuL
LCuB(pin) RCHO
LCuB(pin) R B(pin)
OB(pin)
(pin)BB(pin)
without diboron
R CuL
OB(pin)
facile isomerizationvia boryl migration
path A
path B
1a 5, 91%
4
L = IPr
6 3
3
7
1,2-boryladdition
B(pin)
CuL
181
The mechanistic study of the NHC‐borylcopper(I) catalytic system by Lin
and Marder revealed a pathway that consists of a 1,2‐boryl addition (4→6),
diboration (6→3), and isomerization (6→7).5 However, Scheme 3 illustrates
several additional points that need to be addressed in the particular case of
an asymmetric carbonyl borylation with a chiral diphosphine ligand. The
regioselectivity for the addition of a diphosphine‐borylcopper(I) complex to a
polarized C=O double bond (1,2‐addition vs 2,1‐addition) in the first step
needs to be further investigated (Scheme 3a). Although similar theoretical
studies on the NHC‐borylcopper(I) complex have already been reported by
Lin and Marder, the differences in the reactivity of the diphosphine‐ and
NHC‐complex is yet to be fully explained. The mechanism for the
enantioselective formation of products in the reaction between the
borylcopper(I)/(R)‐DTBM‐SEGPHOS complex and the aldehydes will also be
discussed (Scheme 3b). This particular enantioselectivity is only attributed to
the (R)‐DTBM‐SEGPHOS ligand since similar chiral ligands such as
(R)‐SEGPHOS have given poor experimental results. In addition, our
previous study showed that the presence of a proton source was critical to
the experimental outcome of the reaction (Scheme 3c). Although the proton
source does not participate in the borylation step, the yields and ee values
were significantly lowered in the presence of i‐PrOH or in the absence of
MeOH. An investigation of the effects of a proton source in these reactions
has never been reported. To fill these gaps in knowledge (outlined in Scheme
CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %)
CH2Cl2, rt, 3 h
1b R H
BHOPh H
O
B BO
O O
O+
2(1.0 equiv)
MeOH (2.0 equiv)THF, 30 C, 6 h
OO
BnMe2SiCl (1.0 equiv)imidazole (3.0 equiv)
Ph H
BBnMe2SiO OO
(R)-DTBM-SEGPHOS72%, 96% ee
(S)-8
O
O
O
O
PAr2
PAr2
Ar = 3,5-di-t-Bu-4-MeO-C6H2
unstabe
182
3), we decided to further elucidate the detailed reaction mechanism for the
chiral diphosphine/copper(I)‐catalyzed enantioselective borylation of a
polarized C=O double bond using DFT calculations.
Scheme 3. Factors That Were Not Fully Addressed in Previous Studies
Results and Discussion
All calculations were performed with a Gaussian 09W (revision C.01)
program package.11 Geometry optimizations were performed using
B3PW91/cc‐pVDZ in the gas‐phase. The molecular orbitals were drawn with
a GaussView 5.0 program. The transition states (TS) were confirmed based
on the presence of one imaginary frequency at their normal vibrational
modes. The intermediates (I), reactant complexes (RC), and products were
confirmed as local minima based on all of the positive frequencies. The
intrinsic reaction coordinate (IRC) was calculated for the transition states to
confirm that the structures were indeed connected by two relevant minimas.
a) Origin of regioselectivity in the diphosphine/borylcopper(I) complex
CuB(pin)
P
P
O CH
RO C
Cu
R
B(pin)P
P
HO C
(pin)B Cu
HR2
PP
2,1-addition 1,2-addition
minor major
b) Mechanism of enantioselection
(R)-DTBM-SEGPHOS
(R)-SEGPHOSPh H
(S)-8
B(pin)BnMe2SiO 72%, 96% ee
74%, 24% ee
CuCl / L* (5 mol %) 2 (1.0 equiv)
1b
Ph H
O
K(O-t-Bu), MeOHthen silylation
c) Effect of proton source in the enantioselective borylation
with MeOH: 6 h, 72%, 96% ee
without MeOH:24 h, 34%, 22% eeL * = (R)-DTBM-SEGPHOS
Ph H
(S)-8
B(pin)BnMe2SiOCuCl / L* (5 mol %) 2 (1.0 equiv)
1b
Ph H
O
K(O-t-Bu), MeOHthen silylation
with i-PrOH:6 h, 28%, 53% ee
183
In addition, the energy profiles were derived from the free energies of
formation at 298.15 K.
Investigation on the Origin of Regioselectivity
To reveal the origins for the regioselectivity of the
diphosphine/borylcopper(I) complex, we carried out the DFT calculation by
employing an simplified model, achiral borylcopper(I)/Me2PCH=CHPMe2
model complex with the substrate, formaldehyde (Figure 1). The two
regioisomeric pathways for the insertion of borylcopper(I) into formaldehyde
were investigated. The free energy of activation for the disfavored path B
(TSB minor) was higher than path A (TSA major) by +23.0 kcal/mol. Furthermore,
the π‐complex, IIIminor, in path B was significantly destabilized by +8.9
kcal/mol in comparison to IIImajor in path A. However, the addition product,
P1minor, was stabilized in path B by 10.6 kcal/mol compared to P1major in path
A. These results indicate that the diphosphine/copper(I)‐catalyzed borylation
of aldehydes proceeds under a kinetically controlled mechanism (path A),
which can lead to the 1,2‐boryl addition product, LCu‐OCH2‐B(O2C2H4)
(P1major). Thus, the author found that the regioselectivity trends for the
diphosphine‐borylcopper(I) complex were similar to those for the NHC
complex catalyst studied by Lin and Marder.5
Figure 1. DFT Calculation (B3PW91/cc‐pVDZ) of the Aldehyde Addition Step
in the Diphosphine/copper(I) Catalyzed Borylation Reaction. Gibbs Free
Energy Values Relative to the Starting Model Compounds, I and II, are
Shown in kcal/mol at 298 K and 1.0 atm in the Gas Phase.
184
HOMO‐LUMO orbital analysis gave an explanation for the large difference
in the activation energy between TSA major and TSB minor (Figure 2). The result
shows that the HOMO orbitals of the borylcopper(I) complex I are primarily
located in the CuB σ bond, which imparts a nucleophilic character to
complex I (Figure 2a). The contribution of the carbon 2p orbital to the LUMO
orbital of complex I is significantly greater than the contribution of the
oxygen 2p orbital in formaldehyde II (Figure 2b). Thus, P1major is favored
C OH
H+
Cu B(eg)P
P
C OHH
CuPP
B(eg)
O C
CuPP
B(eg)
H
H
I
II
+ 10.3
+ 1.40
C OH
H
CuPP
B(eg)
O C
CuPP
B(eg)
HH
+ 29.7
+ 6.7
O C
CuP
P
B(eg)
HH
19.9
30.5
C O
CuP
P
B(eg)
HH
G (
kca
l/mo
l)
IIImajor
IIIminor
TSB minor
TSA major
P1major
P1minor
disfavored path B
favored path A
P
P=
PMe2
PMe2
185
since the activation barrier for TSA major is smaller than TSB minor. This complex
is more stabilized due to the larger orbital overlap between the HOMO of
borylcopper(I) and the LUMO of the C=O double bond in the transition state
(Figure 2c and d).12,13
Figure 2. (a) HOMO of Borylcopper(I) Complex I. (b) LUMO of
Formaldehyde II. (c) HOMO of TSA major. (d) HOMO of TSB minor.
(a) (b)
(c) (d)
The structural parameters for the TSA major and TSB minor transition states
are shown in Figure 3. The lengths of both the CuO and BC bonds in the more favorable TSA major pathway are relatively short (2.01 and 2.00 Å,
respectively).14 This indicates that there is reasonable strength of interaction
between borylcopper(I) and the substrate. In contrast, TSB minor has a
noticeably shorter distance between the boron atom and the carbonyl oxygen
(1.87 Å) and a relatively longer distance between the copper center and the
carbonyl carbon (2.09 Å). Because the copper center has weaker interaction
with the substrate than TSA major, the insertion of the complex is disfavored. In
addition, the bond angle (Cu B O) for TSB minor (59.54 ) is significantly
smaller than TSA major (69.01 ), which is most likely observed because of the
strong interaction between boron and the carbonyl oxygen. This structure
strain causes significant destabilization of the complex due to the distortion
of the TSB minor structure. These structural features are all consistent with the
Cu BP
PI
O
OO C
IIHH
O C
CuPP
B
HH
TSA major
OO
C O
CuPP
B OO
HH
TSB minor
186
regioselectivity trends observed in the HOMO‐LUMO orbital analysis.
Figure 3. Calculations of the Selected Bond Lengths and Angles for TSA major
and TSB minor
The author have conducted activation strain model (ASM) analysis to
obtain deeper understanding on the regioselectivity issue (Table 1).15 The
energies to deform the isolated reactants to the transition geometry (Edist)
and the energy of interaction between these deformed reactants are
summarized as shown below. The deformation energy of favored
1,2‐addition pathway A (30.58 kcal/mol) is larger than that of disfavored
2,1‐addition pathway B (24.66 kcal/mol). The interaction energy (Eint) of
1,2‐addition pathway (–23.04 kcal/mol) is significantly larger than that of
2,1‐addition pathway (–9.43 kcal/mol, respectively). This analysis indicates
that the lower activation barrier of the 1,2‐addition pathway compared to
2,1‐addition pathway is attributable to the efficient interaction between
borylcopper(I) complex and formaldehyde in the 1,2‐addition pathway to
stabilize the transition state. This explanation agrees with the result of the
HOMO‐LUMO orbital analysis shown in Figure 2.
187
Table 1. ASM Analysis (B3PW91/cc‐pVDZ) for the Addition Transition States.
Electronic Energies Relative to the Starting Model Compounds, I and II, are
Shown in kcal/mol at 298 K and 1.0 atm in the Gas Phase
Investigation on the Mechanism for Enantioselectivity.
The author previously reported that a high enantioselectivity was
obtained (96% ee) for the borylation of an aliphatic aldehyde 1b with a
(R)‐DTBM‐SEGPHOS chiral ligand. In contrast, the less sterically
encumbered (R)‐SEGPHOS ligand gave a significant decrease in the
enantioselectivity (24% ee) of the reaction (Scheme 4).
Scheme 4. Comparison of Enantioselectivities in the Borylation of Aldehydes
with SEGPHOS‐Type Chiral Ligands
Edist
Eint
E
C OH
HCu B(eg)
P
P I II+
C OHH
CuPP
B(eg)
TSB minor
O C
CuPP
B(eg)
HH
TSA major
favored path A
EdistE Eint
disfavored path B
7.54 30.58 23.04
15.28 24.66 9.43
reaction path
favored path A
O CCuP
P
B(eg) HH
C OH
HCuP
P
B(eg)
disfavored path B
P
P=
PMe2
PMe2
188
DFT calculations (B3PW91) were used to explain the substituent effects
of SEGPHOS‐type ligands for the enantioselective borylation of aldehydes
(Figure 4). The results showed that the activation barrier for the Re‐face
addition of (R)‐DTBM‐SEGPHOS/borylcopper(I) to acetaldehyde in the
transition state TS2 was higher than the Si‐face addition for the transition
state TS1 by +1.97 kcal/mol. In the case of a Si‐face attack, the transition state
TS1 is free from steric congestion between the t‐Bu group on the ligand
(displayed in blue on Figure 4a) and the acetaldehyde substituent. This
produces an (S)‐isomer as a major enantiomer, which agrees with the
observed absolute configuration of the borylated product. In contrast, the
unfavored transition state TS2 is destabilized because the substituent on
acetaldehyde is sterically hindered by one of the t‐Bu groups on the ligand.
This results in a higher activation barrier for TS2. The author also performed
similar calculations with the less sterically hindered (R)‐SEGPHOS ligand. As
previously mentioned, this ligand gave a poor enantioselectivity for the
borylation of the aliphatic aldehyde 1b (Figure 4b). The disfavored transition
state TS4 is destabilized less than TS2 because the acetaldehyde substituent
is relatively far from the phenyl groups on the ligand. Thus, the energy
difference between TS3 and TS4 is smaller than that between TS1 and TS2.
This indicates that enantioselectivity is largely controlled by the steric effects
between the t‐Bu group on the ligand and the substituent on the aldehyde.
O
O
O
O
P
P
tBu
OMe
tButBu
OMetBu
2
2
(R)-DTBM-SEGPHOS
O
O
O
O
P
P2
2
(R)-SEGPHOS
CuCl (5 mol %)L* (5 mol %) 2 (1.0 equiv)
1bR H
(S)-8
B(pin)HOPh H
O
96% ee 24% ee
MeOH (2.0 equiv)K(O-t-Bu)/THF30 C 6 h
BeMe2SiClimidazole
CH2Cl2, rtPh H
B(pin)BnMe2SiO
unstable ee (%)
189
Figure 4. DFT Calculations (B3PW91/cc‐pVDZ) of the Transition States for the
(R)‐DTBM‐SEGPHOS and (R)‐SEGPHOS/Copper(I)‐Catalyzed
Enantioselective Borylation of Acetaldehyde. Relative G Values (kcal/mol)
were Obtained at 298 K and 1.0 atm in the Gas Phase.
(a)
(b)
190
Investigation on the Effect of a Proton Source in the Enantioselective
Borylation of Aldehydes
In the previous study, the author found that a proton source has a great
impact on the reactivity and enantioselectivity of the copper(I)‐catalyzed
borylation of a C=O double bond.15 The use of i‐PrOH instead of MeOH
resulted in a low yield (28%) and enantioselectivity (53% ee) (Scheme 5a). A
reaction in the absence of MeOH did not reach completion of the reaction
even with a longer reaction time (24 h). The product with a lower yield (34%)
and a lower enantioselectivity (22% ee) (Scheme 5a) was thus obtained. The
proposed reaction mechanism for the reaction in the absence of a proton
source was shown in Scheme 5b. The author speculates that the reaction of
the addition intermediate (S)‐9 with the diboron compound 2 to give the
borylated product (S)‐3 would be slow due to the significant steric
interaction between the bulky (S)‐9 complex and the B(pin) group in 2.17,18
The isomerization from (S)‐9 to a more thermodynamically stable
intermediate (R)‐10 would also proceed. A further reaction with 2 gives the
191
opposite enantiomer (R)‐3 through the net stereoinversion reaction in terms
of the CB bond.17 As for the use of sterically hindered i‐PrOH, the relatively
slow protonation of intermediate (S)‐9 could lead to the isomerization of
(S)‐9 to (R)‐10, which decreases the enantiomeric excess of the borylation
product.19
Scheme 5. Impact of the Proton Source on the Copper(I)‐Catalyzed
Enantioselective Borylation of Aldehydes
To confirm the isomerization pathway, the author performed a DFT
calculation (B3PW91/cc‐pVDZ) using a borylcopper(I)/Me2PCH=CHPMe2
model complex and the model substrate, formaldehyde (Figure 5,
isomerization path). The result showed that the activation energy required
for isomerization was 18.5 kcal/mol, which was a reasonable value in light of
the current reaction conditions. The isomerization of (S)‐9 explains why
racemized products can be observed after the reaction.
1. CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %) alcohol (2.0 equiv) THF, 30 C
2. BnMe2SiCl (1.0 equiv) imidazole (3.0 equiv) CH2Cl2, 3 h
1b
Ph H
(S)-8
B(pin)BnMe2SiO
Ph H
O
B BO
O O
O+
2(1.0 equiv)
with MeOH: 6 h, 72%, 96% ee
without MeOH: 24 h, 34%, 22% ee
L* = (R)-DTBM-SEGPHOS
O C
Cu
R
B(pin)P
P
O C
(pin)B
R
B(pin)
H
H
(pin)B B(pin)
LCuB(pin)
O CRH
Cu
B
P P
O CR
H(pin)B
Cu
PP
O CR
H(pin)B
B(pin)(R)+ (S)
(S)-9
(S)-3
(R)-10
22
(R)-3
opposite enantiomer(racemizaton pathway)
relativelyslow
isomerizationintermediate
a) Effect of proton source
b) Proposed mechanism
B(pin)migration
with i-PrOH: 6 h, 28%, 53% ee
LCuB(pin)+
192
Figure 5. DFT calculations (B3PW91/cc‐pVDZ) of the isomerization pathway
and the protonation pathway with MeOH. Gibbs free energy values relative
to P1major are shown in kcal/mol at 298 K and 1.0 atm in the gas phase for the
isomerization step. Gibbs free energy values relative to the total energy of
P1major and MeOH are shown in kcal/mol at 298 K and 1.0 atm in the gas
phase for the protonation step.
The author also found that the activation barrier for the protonation of the
addition complex P1major by MeOH was relatively low [ΔG (TSDIV) = +2.5
kcal/mol]. This indicates that the isomerization pathway can be suppressed
by facile protonation in the presence of MeOH (Figure 5, protonation path).
However, the free energy of the protonation product P2 is higher than P1major,
G (
kcal
/mol
)
O C
CuP
P
B(eg)
HH
P1major
0
O CCuP
P B(eg)
HH
TSB
O
CCu B(eg)
H HP
P
TSC
C O
CuP
P
B(eg)
HH P1minor
+ 4.2
+ 18.5
10.6
5.4
O C
CuP
PB(eg)
HH
HMeO
OC
Cu
P P
B(eg)
HHH
MeO
2.9IV
TSD
+ 1.76
CHO HH
+
Cu OMeP
P VB(eg)
P2
isomerization path(no MeOH)
protonation path(in the presence of MeOH)
+ MeOH
P
P=
PMe2
PMe2
193
which is most likely due to the use of a small model complex I and aldehyde
II. The author then performed a DFT calculation on the protonation step by
using the sterically bulky ligand, (R)‐DTBM‐SEGPHOS, and the substrate,
butyl aldehyde (Scheme 6). Although the transition state between the
addition complex P3 and L*CuOMe P4 could not be determined, the
activation energy for the protonation step would be very low as shown in
Figure 5. The author found that the total energy for the intermediate P3 and
MeOH was higher than LCuOMe and the protonation product P4. This is
most likely observed because of the larger steric congestion in P3 than in P4.
This result suggests that the steric effects of the ligand can facilitate the
protonation process in a thermodynamically controlled reaction to suppress
side reactions such as isomerization. The subsequent reaction of P4 with
diboron is much faster than the reaction of P3 with diboron to regenerate
LCuB(pin).17 Thus, the product is obtained with a higher yield and
enantioselectivity in an (R)‐DTBM‐SEGPHOS/copper(I)‐catalyzed borylation
with a proton source.
Scheme 6. DFT Calculation (B3PW91/cc‐pVDZ) of the Protonation Step using
a (R)‐DTBM‐SEGPHOS Complex
O
O
O
O
P
PCu
tBu tBuOMe
tBu
tBu
OMe
OMe
tBu tButBu
OMe
tBu
OB(pin)
Me
MeOH
+
O
O
O
O
P
PCu
tBu tBuOMe
tBu
tBu
OMe
OMe
tBu tButBu
OMe
tBu
OMe
OH
(pin)B
+
protonation
leading to morestable intermediate
0 kcal/mol 9.0 kcal/mol
P3 P4
11
194
Conclusion
In this study, the author successfully elucidated the origin for the
regioselectivity, the mechanism for the enantioselectivity, and the effect of a
proton source in the copper(I)‐catalyzed nucleophilic borylation of a
polarized C=O double bond. Scheme 7 shows the proposed catalytic cycle
based on these theoretical investigations. The borylcopper(I) active species B,
which was generated through the reaction of copper(I) alkoxide A and a
diboron reagent 2, reacts with aldehydes to form the coordinated complex C.
A 1,2‐addition reaction then occurs to generate the boryl addition complex E.
Analysis of the HOMO‐LUMO orbitals revealed that the orbital interactions
between borylcopper(I) and the C=O double bond in the 1,2‐addition
transition state were stronger than a 2,1‐addition transition state that
facilitates the formation of LCu‐OCHR‐B(pin) E (Scheme 7a). A
borylcopper(I)/(R)‐DTBM‐SEGPHOS complex and the substrate,
acetaldehyde, were used in the enantioselectivity model. It was discovered
that the steric hindrance between the t‐Bu group on the ligand and the
substituent on acetaldehyde in the transition state D largely influences the
enantioselectivity of the reaction (Scheme 7b). The author also found that
rapid protonation of the sterically hindered LCu‐OCHR‐B(pin) E
intermediate with MeOH under a thermodynamically controlled reaction
provided the product F and copper(I) alkoxide A. The presence of MeOH
suppresses an isomerization pathway that causes a decrease in the
enantioselectivity of the generated products (Scheme 7c). Although the
metathesis reaction between E and a diboron reagent can still generate the
product, addition of MeOH causes a faster protonation of E to provide the
product and the copper(I) alkoxide A. This theoretical study on the
mechanism for the enantioselective borylation of a polarized
carbon‐heteroatom bond will be valuable for the further development and
rational design of novel copper(I)‐catalyzed nucleophilic borylation
reactions.
195
Scheme 7. Proposed Catalytic Cycle based on Our Current Theoretical Study
Cu B(pin)P
P
(pin)BOR
-bondmetathesis
coordination
CuP
P
2
1
A
B C
D
CuB(pin)
P
P
O CH
R
B(pin)*LCu
CO RH
a) Regioselectivity
efficient orbitalinteraction
b) Enantioselection
steric effect of t-Bu groupin (R)-DTBM-SEGPHOS
O C
Cu
R
B(pin)P
P
H
1,2-addition
E
OR
MeOH
O C
H
R
B(pin)
HF
c) Protonation effect
suppress the isomerizationleading to opposite enantiomer
isomerization(without alcohol)
(pin)B
CO
HR
CuL**
P
P= (R)-DTBM-SEGPHOS
R = OMe or O-t-Bu
196
Details of DFT Calculations
All calculations were performed using the Gaussian 09W (revision C.01)
program package.20 Geometry optimizations and transition states (TS)
calculations were performed with B3PW91/cc‐pVDZ in the gas‐phase.
Molecular structures were drawn using the Mercury 3.5 program.21
Frequency calculations were conducted on gas‐phase optimized geometries
to check the all the stationary points as either minima or transition states.
Optimized Structures, Calculated Energies, and Thermochemical
Parameters
a) Aldehyde addition step
II
I
IIImajor
IIIminor
TSA major P1major
TSB minor P1minor
Cu
B
P O
B Cu
O
Cu
B
O
C
Cu
O C
B
O
C
Cu
B Cu
C O
B
Cu C
O
B
b) Protonation path
IV TSO
V
P2
c) Isomerization path
TSB TSC
Cu
B P O
Cu
O
O
O
C
H
B
H
Cu
O
B
Cu O
B Cu
O B
C
197
Figure S1. Optimized Structures for Aldehyde Addition Step (a),
Protonation Step (b), Isomerization Step (c), and Protonation Step using
(R)‐DTBM‐SEGPHOS Complex (d).
198
Table S1. Calculated Energies and Thermochemical Parameters of the
Optimized Structures
E / Hartree H / Hartree S / Hartree Ga / kcal mol‐1
Aldehyde addition step
I ‐2813.883360 ‐2813.862939 ‐2813.861994 ‐1765771.928
II ‐114.436103 ‐114.433234 ‐114.432289 ‐71822.92826
IIImajor ‐2928.336108 ‐2928.312845 ‐2928.311901 ‐1837593.495
TSA major ‐2928.330286 ‐2928.308188 ‐2928.307244 ‐1837588.14
P1major ‐2928.369879 ‐2928.347228 ‐2928.346284 ‐1837614.791
IIIminor ‐2928.323026 ‐2928.299793 ‐2928.298849 ‐1837584.54
TSB minor ‐2928.293971 ‐2928.271905 ‐2928.270961 ‐1837565.161
P1minor ‐2928.386599 ‐2928.363996 ‐2928.363052 ‐1837625.34
Enantioselection
TS1 ‐6209.916750 ‐6209.814302 ‐6209.813358 ‐3896870.421
TS2 ‐6209.913372 ‐6209.811084 ‐6209.810140 ‐3896868.455
TS3 ‐4495.456261 ‐4495.408645 ‐4495.407701 ‐2820994.423
TS4 ‐4495.454868 ‐4495.407339 ‐4495.406395 ‐2820993.378
Protonation path
IV ‐3044.024403 ‐3043.997283 ‐3043.996339 ‐1910193.847
TSD ‐3044.024571 ‐3043.998553 ‐3043.997609 ‐1910191.345
P2 ‐368.896500 ‐368.889054 ‐368.888110 ‐231506.8552
V ‐2675.098743 ‐2675.080983 ‐2675.080038 ‐1678679.817
Isomerization path
TSB ‐2928.364644 ‐2928.342609 ‐2928.341665 ‐1837610.545
TSC ‐2928.341745 ‐2928.319601 ‐2928.318656 ‐1837596.292
Protonation step using (R)‐DTBM‐SEGPHOS complex
P3 ‐6445.610318 ‐6445.499212 ‐6445.498268 ‐4044777.93
MeOH ‐115.630729 ‐115.627420 ‐115.626476 ‐72573.64486
P4 ‐5917.417646 ‐5917.320356 ‐5917.319411 ‐3713322.531
11 ‐643.830915 ‐643.814144 ‐643.813200 ‐404038.0495
aRelative G values (kcal mol‐1) at 298 K, 1.0 atm, gas phase.
199
References and Notes
(1) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2nd revised ed.; Hall, D. G., Ed.; Wiley‐VCH:
Weinheim, 2011.
(2) The early examples of copper(I)‐catalyzed borylation reaction, see: (a) Ito,
H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41,
6821 6825. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000,
982 .
(3) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128,
11036 11037.
(4) Molander, G. A.; Wisniewski, S. R. J. Am. Chem. Soc. 2012, 134,
16856 16868.
(5) Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130,
5586 5594.
(6) Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 420 424.
(7) The selected examples of copper(I)‐catalyzed enantioselective borylation
reaction, see: (a) Lee, J.‐E.; Lee, J.‐E.; Yun, J.; Yun, J. Angew. Chem., Int. Ed.
2008, 47, 145 147. (b) Lillo, V.; Prieto, A.; Bonet, A.; Diaz ‐Requejo, M. M.;
Ramirez, J.; Perez, P. J.; Fernandez, E. Organometallics 2009, 28, 659 662. (c)
Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160 3161. (d) Noh, D.;
Chea, H.; Ju, J.; Yun, J. Angew. Chem. Int. Ed. 2009, 48, 6062 6064. (e) Chen,
I.‐H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
11664 11665. (f) Moure, A. L.; Gómez Arrayás, R.; Carr etero, J. C. Chem
Commun. 2011, 47, 6701 6703. (g) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat.
Chem. 2011, 3, 894 899. (h) Feng, X.;, Jeon, H.; H.; Yun, J. Angew. Chem. Int.
Ed. 2013, 52, 3989 3992. (i) Lee, H.; Lee, B. Y.; Yun, J. Org. Lett. 2015, 17,
764 766.
(8) For our selected studies on copper(I)‐catalyzed enantioselective
borylation reactions, see: (a) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.;
Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856 14857. (b) Ito, H.; Kosaka,
Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47,
74247427. (c) Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc.
2010, 132, 1226 1227. (d) Ito, H.; Okura, T.; Matsuura, K.; Sawamura, M.
Angew. Chem., Int. Ed. 2010, 122, 570573. (e) Ito, H.; Kunii, S.; Sawamura, M.
Nat. Chem. 2010, 2, 972 . (f) Kubota, K.; Yamamoto, E.; Ito, H. Adv.
200
Synth. Catal. 2013, 355, 3527. (g) Yamamoto, E.; Takenouchi, Y.;
Ozaki, T.; Miya, T.; Ito, H. J. Am. Chem. Soc. 2014, 136, 1651516521.
(9) Asymmetric copper(I)‐catalyzed borylations of C=N bonds, see: (a) Beene,
M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 691016911. (b) Wen,
K.; Wang, H.; Chen, J.; Zhang, H.; Cui, X.; Wei, C.; Fan, E.; Sun, Z. J. Org.
Chem. 2013, 78, 3405 3409. (c) Zhang, S.‐S.; Zhao, Y.‐S.; Tian, P.; Lin, G.‐Q.
Synlett 2013, 24, 437442.
(10) Non‐enantioselective nucleophilic borylations of carbonyl compounds
through copper(I) catalysis, see: (a) Mclntosh, M. L.; Moore, C. M.; Clark, T. B.
Org. Lett. 2010, 12, 1996 1999. (b) Moore, C. M.; Medina, C. R.; Cannamela, P.
C.; McIntosh, M. L.; Ferber, C. J.; Roering, A. J.; Clark, T. B. Org. Lett. 2014, 16,
6056 6059.
(11) Gaussian 09, Revision C.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian,
H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro,
F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J.
E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann,
R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin,
R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009.
(12) Dang, L.; Zhao, H.; Lin, Z.; Marder, T. B. Organometallics 2007, 26,
2824 2832.
(13) Ito’s previous mechanistic studies in copper(I)‐catalyzed borylation
based on HOMO‐LUMO orbital analysis, see: (a) Sasaki, Y.; Horita, Y.; Zhong,
C. M.; Sawamura, M.; Ito, H. Angew. Chem.; Int. Ed. 2011, 50, 27782782. (b)
Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2013, 135, 26352640.
(14) The calculated standard bond lengths of Cu O bond and C B bond
are 1.84 Å and 1.57 Å, respectively.
(15) Fernández, I.; Bickelhaupt, F. M. Chem. Soc. Rev. 2014, 43, 4953 4967.
201
(16) Yun first reported the rate acceleration by alcohol additives in
copper(I)‐catalyzed borylation, see: Mun, S.; Lee, J. ‐E.; Yun, J. Org. Lett. 2006,
8, 4887 4889.
(17) Lin and Marder reported that the DFT study of the metathesis of
copper(I) alkoxide or alkylcopper(I) model complexes with a diboron
compound, see: Dang, L.; Lin, Z.; Marder, T. B. Organometallics 2008, 27,
4443 4454.
(18) The author have experimentally observed that the reaction rate of the
DTBM‐SEGPHOS/copper(I)‐catalyzed borylation without MeOH is slower
than that of the protonation reaction with MeOH, as aldehyde substrate 1b
still remained(23% recovery of 1b)even after 24 h while full conversion of 1b
was observed within 6 h in the reaction with MeOH. In the absence of MeOH,
the product is produced by both the metathesis of (S)‐9 and B2pin2 and the
isomerization [(S)‐9 to (R)‐10 to (R)‐3]. These results suggest that the
metathesis of (S)‐9 and B2pin2 is much slower than the protonation pathway
in the presence of MeOH. The isomerization was reported to proceed easily
(ref. 3) and the calculate activation energy (18.5 kcal/mol) is roughly
comparable the reaction rate in the absence of MeOH. These results suggest
that the isomerization pathway is comparable to the metathesis pathway,
contributing the low ees of the product.
(19) The author cannot completely exclude the possibility that an alcohol
molecule would be involved in the addition transition state at this stage.
However, it is unlikely that the coordination of an alcohol to the copper(I)
center because the copper(I) intermediate in the transition state is
coordinatively saturated 18‐electron complex. In addition, the author have
confirmed that the borylation of 1b using a polar solvent such as DMI to
check the polarity effect of an alcohol on the enantioselectivity resulted in no
reaction. Thus, we argued that the significant alcohol effect is attributable to
the facile protonation of (S)‐9 to suppress the isomerization‐induced
racemization.
(20) Gaussian 09, Revision C.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian,
H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J., J. A.; Peralta, J.
202
E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov,
V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.
C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador,
P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.;
Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian, Inc., Wallingford CT, 2009.
(21) Mercury:
http://www.ccdc.cam.ac.uk/Solutions/CSDSystem/Pages/Mercury.aspx
203
Chapter 6.
Copper(I)‐Catalyzed Enantioselective Borylative
Dearomatization of Indoles
204
Abstract
The first enantioselective borylative dearomatization of a heteroaromatic
compound has been achieved using a copper(I) catalyst and a diboron
reagent. This reaction involves the unprecedented regio‐ and enantioselective
addition of borylcopper(I) active species to indole‐2‐carboxylates, followed
by the diastereoselective protonation of the resulting copper(I) enolate to
give the corresponding chiral indolines bearing consecutive stereogenic
centers.
Introduction
Aromatic compounds are ubiquitous in nature and readily available as
synthetic materials. The enantioselective dearomatization reactions of
heteroaromatic compounds are very powerful transformations because they
can be used to provide direct access to a wide variety of chiral‐saturated
heterocycles, which are important components of pharmaceutical drugs and
bioactive molecules.1 The development of new methods for the formation of
consecutive stereogenic centers via the stereoselective dearomatization of
multi‐substituted aromatic compounds would also have important practical
implications for the synthesis of natural products.2
Enantioenriched organoboron compounds are recognized as useful chiral
building blocks in synthetic chemistry because they can be readily applied to
the stereospecific functionalization of stereogenic C–B bonds.3 Considerable
research efforts have recently been devoted to the development of new
methods for the metal‐catalyzed enantioselective hydro‐ and protoboration
reactions of prochiral C=C double bonds.4,5 Despite significant progress in
this area, there have been no reports pertaining to the development of C–B
bond‐forming dearomatization reactions. The lack of research in this area is
most likely caused by the high energy barrier encountered during the
dearomatization process.1 The development of an enantioselective C–B
bond‐forming dearomatization reaction would provide an attractive and
complementary approach for the synthesis of complex, functionalized cyclic
molecules in combination with the stereospecific transformation of a
stereogenic C–B bond.
205
Ohmura et al.6 and Weetman et al.7 independently reported the results of
their pioneering studies towards the development of a borylative
dearomatization reaction, where pyridines were subjected to a dearomative
hydroboration reaction with pinacolborane in the presence of Rh(I) and
Mg(II) catalysts. In 2014, Marks et al.8 reported the development of a similar
reaction using La(III) as a catalyst. However, the authors of these studies
were only able to demonstrate non‐enantioselective N B bond ‐forming
dearomatization reactions.9,10
Herein, we report for the first time the development of a
copper(I)‐catalyzed reaction for the highly regio‐, diastereo‐ and
enantioselective C–B bond‐forming dearomatization of heteroaromatic
compounds (Scheme 1). This reaction involves the unprecedented
enantioselective addition of an active borylcopper(I) species to an
indole‐2‐carboxylate 1, followed by the diastereoselective protonation of the
resulting copper(I) enolate to give the corresponding enantioenriched chiral
indoline derivative 3 with excellent diastereo‐ and enantioselectivities. The
stereospecific oxidation of the chiral 3‐borylindoline product 3 has also been
demonstrated.
Scheme 1. Copper(I)‐Catalyzed Enantioselective C–B Bond Forming
Dearomatization of Indoles
During the last decade, our group has been involved in the development
of new methods for the copper(I)‐catalyzed enantioselective borylation of
prochiral alkenes.11 The results of the related research in this field revealed
that electron‐deficient substrates with low LUMO levels tend to react
efficiently with active borylcopper(I) species.12 Based on these results, it was
cat.Cu(I)/L*
B BO
OO
O
1
2
NR3
+base
NR3
O
OR2
R1B
OCuL
OR2
OO
R4OH
NR3
B
O
OR2
OO
H
up to 98% yieldup to 97% eeup to 97:3 d.r.
3R1
R1
206
envisaged that heteroaromatic systems bearing an electron‐withdrawing
group could also react with a borylcopper(I) complex in a process involving
the formation of a stereogenic C–B bond. With this in mind, a readily
available indole‐2‐carboxylate derivative was selected as a model substrate to
investigate the optimum reaction conditions for the enantioselective
borylative dearomatization of this substrate using a chiral copper(I) catalyst.
This reaction would allow for the synthesis of chiral indolines containing
consecutive stereogenic centers at their 2‐ and 3‐positions. Chiral indolines
can be found in a wide variety of naturally occurring bioactive compounds
and the synthesis of these compounds has consequently attracted
considerable interest from researchers working in a number of different
fields (Figure 1).13,14 The development of an enantioselective dearomative
borylation reaction for indoles would therefore provide an interesting and
efficient approach to this class of enantioenriched heterocycles.
Figure 1. Chiral Indoline‐Based Bioactive Molecules
N
N
Me
HMe
Me
OHN
O
Me
()-Physostigmine
NCO2H
O
CO2Et
Me
Me
pentopril
N
NH WAY-163909
207
Results and Discussion
The results of an extensive series of optimization experiments revealed
that the reaction of carboxybenzyl (Cbz)‐protected methyl
indole‐2‐carboxylate (1a) with bis(pinacolato)diboron (2) (2.0 equiv) in the
presence of Cu(O‐t‐Bu)/(R,R)‐L1 (10 mol %), Na(O‐t‐Bu) (10 mol %) and
t‐BuOH (2.0 equiv), which was used as a proton source, in THF at 30 °C
afforded the desired dearomatization product (S,R)‐3a in high yield (98%),
with excellent diastereo‐ and enantioselectivities (d.r. 97:3, 93% ee) (Table 1,
entry 1).[15] Notably, no product was observed when the reaction was
conducted in the absence of Cu(O‐t‐Bu) or ligand L1 (Table 1, entries 2 and 3).
A lower yield (74%) of the dearomatization product 3a was obtained when
Na(O‐t‐Bu) was omitted from the reaction (Table 1, entry 4), although the
omission of t‐BuOH led to a significant decrease in the yield and
stereoselectivity of the product (33%, d.r. 76:24, 74% ee) (Table 1, entry 5).
The use of the less sterically hindered (R,R)‐BDPP ligand L2 led to a lower
enantioselectivity (74% ee) (Table 1, entry 6). Several other chiral
bisphosphine ligands were also tested in the reaction, including
(R,R)‐QuinoxP* L3, (R,R)‐BenzP* L4 and (R,R)‐Me‐Duphos L5, but they all
showed poor stereoselectivities (Table 1, entries 7 9). No reaction was
observed when the monophosphine‐type chiral ligand (R)‐MOP L6 was used
in the reaction (Table 1, entry 10). A decrease in the loading of the catalyst to
5 mol % did not lead to an erosion in the enantioselectivity (93% ee),
although slight decreases were observed in the product yield (76%) and
diastereoselectivity (d.r. 92:8) (Table 1, entry 11). The bulkiness of the alcohol
was only found to affect the diastereoselectivity of this reaction, because the
use of MeOH provided moderate diastereoselectivity (d.r. 75:25, Table1,
entry 12).
208
Table 1. Optimization Study
1a
10 mol % Cu(O-t-Bu)10 mol % (R,R)-L1
t-BuOH (2.0 equiv) 10 mol % Na(O-t-Bu)THF, 30 C, 1848 h
(S,R)-3a
(pin)BB(pin)
2(2.0 equiv)
+N
O
OMe
B(pin)
Cbz
N
O
OMeCbz
entry conditions yield (%) d.r. ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
standard conditions
no Cu(O-t-Bu)
no (R,R)-L1
no Na(O-t-Bu)
no t-BuOH
(R,R)-L2 instead of (R,R)-L1
(R,R)-L3 instead of (R,R)-L1
(R,R)-L4 instead of (R,R)-L1
(R,R)-L5 instead of (R,R)-L1
(R,R)-L6 instead of (R,R)-L1
5 mol % of Cu(O-t-Bu)/(R,R)-L1
MeOH instead of t-BuOH
98
<5
<5
74
33
98
93
77
71
<5
76
94
97:3
–
–
89:11
76:24
89:11
90:10
91:9
97:3
–
92:8
75:25
93
–
–
93
74
74
27
61
37
–
93
94
P
PMeMe
Me
Me
(R,R)-L5
(R,R)-L1
PP
Me
Me
Me
Me
Me
Me
Me
Me
P
P
Me t-Bu
t-Bu Me
N
N P
P
Me t-Bu
t-Bu Me(R,R)-L3
(R,R)-L4
(R,R)-L2
PP
OMe
PPh2
(R)-L6
209
With an optimized procedure in hand, we proceeded to investigate the
scope of the reaction using a variety of indole substrates (Table 2). The
introduction of an electron‐withdrawing or electron‐donating functional
group at the 5‐position of the indole was well tolerated, with the borylation
reaction affording consistently excellent selectivities (3be). Indoles bearing
a bromo, methoxy or phenyl substituent at their 6‐position also reacted with
high levels of stereoselectivity (3fh). The borylation of an indole bearing an
ethyl ester group (3i) proceeded with high enantioselectivity (95% ee), but
with a lower product yield (52%). The borylation of an indole bearing a
bulky isopropyl ester group (1j) failed to provide any of the desired product
(S,R)‐3j under the optimized conditions. Fortunately, the replacement of
(R,R)‐L1 with (R,R)‐L2 allowed for the borylation of 1j to proceed in good
yield (88% NMR) and excellent stereoselectivity (d.r. 95:5, 90% ee). We
subsequently proceeded to investigate the scope of the protecting group on
the indole. The borylation of tert‐butyloxycarbonyl (Boc)‐protected indole 1k
provided the expected product (S,R)‐3k with the highest enantioselectivity
(98% ee) observed in the current study, although the yield was significantly
decreased (22% NMR). The replacement of (R,R)‐L1 with the less sterically
hindered (R,R)‐L2 led to a significant improvement in the yield (98% NMR)
with good stereoselectivity (d.r. 93:7, 86% ee). Unfortunately, the application
of the optimized conditions to a fluorenylmethyloxycarbonyl
(Fmoc)‐protected indole group failed to provide any of the desired product,
presumably because of the reaction of the acidic proton of the Fmoc group
with Na(O‐t‐Bu), which resulted in the formation of a complex mixture. We
also found that Me‐protected indoles were not applicable to this protocol.
210
Table 2. Substraate Scope
13% (22%)d.r. 94:6, 98% ee
NBoc
B(pin)
O
OMe
(S,R)-3k
NFmoc
B(pin)
O
OMe NMe
B(pin)
O
OMe
(S,R)-3m(S,R)-3lcomplex mixture
(<5%)no product
(<5%)ligand: (R,R)-L1 ligand: (R,R)-L2
95% (98%)d.r. 93:7, 86% ee
74% (93%)d.r. 97:3, 95% ee
(S,R)-3d
NCbz
B(pin)
O
OMe
64% (93%)d.r. 93:7, 95% ee
(S,R)-3b
NCbz
B(pin)
O
OMe
FCl
NCbz
B(pin)
O
OMe
Br
74% (96%)d.r. 97:3, 92% ee
(S,R)-3c
74% (99%)d.r. 97:3, 97% ee
(S,R)-3e
NCbz
B(pin)
O
OMe
MeO
62% (99%)d.r. 93:7, 86% ee
(S,R)-3f
NCbz
B(pin)
O
OMeBr
1b1m
10 mol % Cu(O-t-Bu)10 mol % (R,R)-L1(pin)BB(pin) 2 (2.0 equiv)
t-BuOH (2.0 equiv)10 mol % Na(O-t-Bu)THF, 30 C, 418 h (S,R)-3b3m
N
O
OR3
R4N
O
OR3
R4
B(pin)
(S,R)-3g
NCbz
B(pin)
O
OMe
71% (82%)d.r. 83:17, 89% ee
(S,R)-3h
NCbz
B(pin)
O
OMe
MeO
76% (88%)d.r. 94:6, 93% ee
Ph
52% (55%)d.r. 86:14, 95% ee
(S,R)-3i
NCbz
B(pin)
O
OEt NCbz
B(pin)
O
O
67% (88%)d.r. 95:5, 90% ee
(S,R)-3j[c]
R1
R2
R1
R2
211
The chiral borylation product (S,R)‐3d generated in this study was
subjected to an oxidation reaction, where it was treated with NaBO3 followed
by a silyl protection reaction to give the desired chiral 1,2‐aminoalcohol
(S,R)‐4 in a highly stereoselective manner (d.r. >99:1, 94% ee, Scheme 2). It is
noteworthy that it would not be possible to synthesize this product using
existing dearomative oxidation methods.16
Scheme 2. Stereospecific Oxidation
The enantioselective borylation of the 2‐methyl indole that does not
contain an ester group (1o) resulted in no reaction (Scheme 3a).17 Preliminary
density functional theory (DFT) calculation (B3PW91/cc‐pVDZ) was used to
explain the effect of substituents at the 2‐position in the substrate (Scheme
3b).18 The results show that the LUMO level of 1a (–1.51 eV) was considerably
lower than the LUMO+1 level of 1o (–0.68 eV), which is localized in the
reactive site, indicating that the electron‐withdrawing ester moiety would
facilitate the addition of borylcopper(I) intermediate to the indoles.
Scheme 3. a) Borylation of 2‐Me‐Indoles with Copper(I) Catalysis. (b) The
Reactive Vacant Orbital Levels of 1a and 1o (B3PW91/cc‐pVDZ).
a)
NCbz
B(pin)
O
OMe
F NaBO34H2O(4.0 equiv)
THF/H2O, 2 hwork up thenTBSCl (1.5 equiv)imidazole (3.0 equiv)d.r. 97:3, 95% ee
(S,R)-3d
NCbz
OTBS
O
OMe
F
(S,R)-464%, d.r. >99:1
94 %ee
10 mol % Cu(O-t-Bu)10 mol % (R,R)-L1
t-BuOH (2.0 equiv)10 mol % Na(O-t-Bu)THF, 30 C, 24 h
1o
NMe
Cbz
(pin)BB(pin)
(2.0 equiv)
+2 N
Me
Cbz
B(pin)
not detected(<5%)
3o
212
b)
A mechanism was proposed for the current copper(I)‐catalyzed
dearomative borylation of indoles (Figure 2). Cu(O‐t‐Bu) A would initially
react with diboron reagent 2 to form the borylcopper(I) B. The coordination
of indole 1a to the copper center would result in the formation of ‐complex
C. The subsequent 3,4‐addition of B into 1a would give the copper(I)
C‐enolate and then transform to the O‐enolate D with concomitant formation
of a stereogenic C B bond. [18] After the formation of D, the bulky t‐BuOH
additive would access D from the opposite side of the pinacolate boryl group
to avoid steric congestion between the B(pin) and t‐Bu groups. The
subsequent diastereoselective protonation of D would proceed via a
six‐membered ring transition state E to provide the dearomatization product
(S,R)‐3a and the Cu(O‐t‐Bu) precatalyst A.
1a
NCbz
O
OMe
1o
NMe
Cbz
213
Figure 2. Proposed Reaction Mechanism
A preliminary DFT calculation (B3PW91/cc‐pVDZ) was performed to
elucidate the mechanism of the dearomatization step in this reaction (Figure
3).18 The results showed that the activation energy for the addition of
borylcopper(I) I to indole II to furnish the copper(I) C‐enolate IV was +18.0
kcal/mol, which was in agreement with the proposed pathway (Figure 2).18
Cu BP
P
P
P= (R,R)-L1
(pin)B(O-t-Bu)
-bondmetathesis
3,4-addition andtautomerization
NCbz
O
OMeCu B
PP
NCbz
O
OMeBPP
NCbz
O
OMeB
HO
HO
coordination
Cu(O-t-Bu)P
P
diastereoselectiveprotonation
2
1a
HO
disfavored
favored
N
B
OMe
OCbz(S,R)-3a
H
Cu
Cu
PP
A
BC
D
E
214
Figure 3. DFT Calculation on the Dearomatiztion Step
Conclusion
In summary, we have developed the first enantioselective C–B
bond‐forming dearomatization of heteroaromatic compound using a chiral
bisphosphine‐copper(I) complex catalyst and a diboron reagent. This reaction
involved the unprecedented enantioselective dearomative addition of
borylcopper(I) to methyl indole‐2‐carboxylate with concomitant formation of
a stereogenic C–B bond, followed by the diastereoselective protonation of the
copper(I) enolate intermediate to deliver the enantioenriched chiral indoline
bearing consecutive stereogenic centers with excellent regio‐, diastereo‐ and
enantioselectivities. The newly synthesized chiral 3‐borylindoline derivative
was successfully transformed to the corresponding chiral 1,2‐aminoalcohol
with high stereospecificity via the oxidation of the C–B bond. The key to the
success of this novel dearomative borylation was the introduction of an
electron‐withdrawing ester group at the 2‐position of the indole, which
effectively promoted the addition of the active borylcopper(I) species to the
215
indole ring. It is envisaged that the results of this study will provide further
opportunities for the development of novel stereoselective dearomative
borylation reactions involving a wide variety of aromatic compounds, such
as pyrroles, furans and polyaromatic hydrocarbons. Advances in this area
would therefore allow for the efficient synthesis of complex saturated
heterocyclic compounds with potentially interesting biological activities.
216
Experimental
General.
Materials were obtained from commercial suppliers and purified by
standard procedures unless otherwise noted. Solvents were also purchased
from commercial suppliers, degassed via three freeze‐pump‐thaw cycles, and
further dried over molecular sieves (MS 4Å). NMR spectra were recorded on
JEOL JNM‐ECX400P and JNM‐ECS400 spectrometers (1H: 400 MHz and 13C:
100 MHz).Tetramethylsilane (1H) and CDCl3 (13C) were employed as external
standards, respectively. CuCl (ReagentPlus® grade, 224332‐25G, ≥99%) was
purchased from Sigma‐Aldrich Co. and used as received. 2‐Phenylethyl
chloride was used as an internal standard to determine NMR yields. HPLC
analyses with chiral stationary phase were carried out using a Hitachi
LaChrome Elite HPLC system with a L‐2400 UV detector. High‐resolution
mass spectra was recorded at the Center for Instrumental Analysis,
Hokkaido University.
General Experimental Procedures
Preparation of Cu(O‐t‐Bu)19
All operations were conducted under argon or nitrogen atmosphere. An
oven‐dried Schlenk flask was charged with CuCl (2.6 g, 26.6 mmol) in an
argon‐filled glovebox. The flask was capped with a rubber septum and
removed from the glovebox. After dry THF (10.0 mL) was added, the
suspension was cooled to −20 °C and a THF solution of 2‐mesitylmagnesium
bromide (0.86 M, 28.1 mL, 24.2 mmol) was added via a syringe. After 15 min,
the reaction mixture was allowed to warm to room temperature, and stirred
CuCl (1.1 equiv)
THF, 20 Crt, 20 h
MgBr
dioxane, benzenert, 20 min
t-BuOH (2.0 equiv)
Cu(O-t-Bu)
Cu
28 Pa, 150 C3 h
sublimation
217
overnight. Dry 1,4‐dioxane (15.0 mL) was added to the reaction mixture and
stirred for 15 min and then allowed to stand without stirring. The resultant
supernatant layer was transferred via cannula to a separate oven‐dried
Schlenk flask through a filter funnel under nitrogen atmosphere. The
precipitated salt was washed with dry benzene. t‐BuOH (4.6 mL, 48.8 mmol)
was then added to the residual solution. After stirring for 20 min, the
solvents were removed in vacuo. The reaction vessel was transferred into a
glove box and then the crude product was transferred from the Schlenk flask
to a sublimation apparatus. The sublimation apparatus was removed from
the glovebox. The crude product was purified by sublimation (bath temp.
150 °C, 28 Pa) to afford Cu(O‐t‐Bu) (0.59 g, 4.3 mmol, 18%). Cu(O‐t‐Bu) is
very sensitive to air and moisture and should be stored and treated in a glove
box.
Preparation of chiral ligands
(R,R)‐L1 was synthesized according to the literature procedure.20 Other
chiral ligands were obtained from commercial suppliers without further
purification.
Procedure for the copper(I)‐catalyzed enantioselective borylative
dearomatization of 1a (Table 1).
1a (155.7 mg, 0.50 mmol) and bis(pinacolato)diboron (253.2 mg, 1.0 mmol),
(R,R)‐3,5‐xyl‐BDPP (27.7 mg, 0.050 mmol) were placed in an oven‐dried
reaction vial. After the vial was placed in a glove box, Cu(O‐t‐Bu) (6.8 mg,
0.050 mmol) and Na(O‐t‐Bu) (4.8 mg, 0.050 mmol) were placed in the vial.
After being sealed with a screw cap containing a teflon‐coated rubber septum,
the vial was removed in a glove box connected to a nitrogen line through a
needle. THF (1.0 mL) was added to the mixture through the rubber septum at
30 °C. Then t‐BuOH (94.9 μL, 1.0 mmol) was added dropwise. After the
reaction was complete, the reaction mixture was passed through a short silica
gel column eluting with Et2O/Hexane (80:20). The crude mixture was
purified by flash column chromatography (SiO2, ethyl acetate/hexane,
typically 4:96–10:90) to give the corresponding borylation product (S,R)‐3a as
a colorless oil.
218
Substrate Preparation
Preparation of 1‐benzyl 2‐methyl 1H‐indole‐1,2‐dicarboxylate (1a).
The Cbz‐protection was performed according to the literature procedure.21
In a 50 mL round bottomed flask, NaH (180.0 mg, 60% dispersion in paraffin
liquid, 4.5 mmol) was dissolved in dry THF (6.0 mL) and the mixture was
cooled to 0 °C under nitrogen atmosphere. Methyl indole‐2‐carboxylate (524.0
mg, 3.0 mmol) was added in three separate times. Benzyl chloroformate (513.9
L, 3.6 mmol) was then added dropwise. After stirred for 4 h at room
temperature, the reaction mixture was quenched by addition of water and
extracted with CH2Cl2 three times. The combined organic layer was then
dried over MgSO4. After filtration, the solvents were removed by evaporation.
The crude product was purified by flash column chromatography (SiO2, ethyl
acetate/hexane, 3:97–10:90) to obtain 1a (659.4 mg, 2.1 mmol, 71%) as a white
solid. 1H NMR (392 MHz, CDCl3, ): 3.73 (s, 3H), 5.42 (s, 2H), 7.13 (s, 1H), 7.28
(d, J = 7.2 Hz, 1H), 7.32 7.49 (m, 6H), 7.60 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 8.6
Hz, 1H). 13C NMR (99 MHz, CDCl3, ): 52.3 ( CH3), 69.6 (CH2), 115.0 (CH),
115.6 (CH), 122.2 (CH), 123.6 (CH), 127.0 (CH), 127.6 (C), 128.6 (CH), 128.7
(CH), 128.8 (C), 130.3 (C), 134.4 (C), 137.6 (C), 150.6 (C), 162.1 (C). HRMS–ESI
(m/z): [M+Na]+ calcd for C18H15O4NNa, 332.08933; found, 332.08934.
NH
O
OMe
1a
N
O
OMe
benzyl chloroformate(1.2 equiv)
NaH (1.5 equiv)THF, 0 Crt, 4 h Cbz
219
Preparation of methyl‐1‐benzyloxycabonyl‐5‐chloro‐indole‐2‐carboxylate
(1b).
The condensation was performed according to the literature procedure.22
In a vacuum dried 100 mL round bottomed flask,
5‐chloro‐indole‐2‐carboxylate (980.2 mg, 5.0 mmol) and
4‐dimethylaminopyridine (DMAP) (612.9 mg, 5.0 mmol), methanol (242.8 L,
6.0 mmol) were dissolved in dry CH2Cl2 (20.0 mL), and the reaction mixture
was cooled to 0 °C under nitrogen atmosphere.
1‐Ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC) (1.15 g, 6.0 mmol)
was then added to the mixture. After stirred for 2 h at room temperature, the
reaction mixture was quenched by addition of HCl aq. (1.0 N) and extracted
with CH2Cl2 three times. The combined organic layer was then dried over
MgSO4, filtered and concentrated under reduced pressure to afford the
corresponding methyl ester (801.1 mg, 3.8 mmol, 76%) as a white solid.
In a 50 mL round bottomed flask, NaH (231.9 mg, 60% dispersion in
paraffin liquid, 5.8 mmol) was dissolved in dry THF (8.0 mL) and the mixture
was cooled to 0 °C. The methyl ester (801.1 mg, 3.8 mmol) was added in three
separate times. Benzyl chloroformate (545.3 L, 3.8 mmol) was then added
dropwise. After stirred for 16 h at room temperature, the reaction mixture
was quenched by addition of water and extracted with CH2Cl2 three times.
The combined organic layer was then dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was purified by
flash column chromatography (SiO2, ethyl acetate/hexane, 4:96–7:93) to
obtain 1b (715.3 mg, 2.1 mmol, 54%) as a white solid. 1H NMR (392 MHz, CDCl3, ): 3.72 (s, 3H), 5.41 (s, 2H), 7.04 (s, 1H), 7.26 (s,
1H), 7.33 7.49 (m, 5H), 7.58 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H). 13C
NMR (99 MHz, CDCl3, ): 52.5 ( CH3), 69.9 (CH2), 114.3 (CH), 116.2 (CH),
NH
O
OH NH
O
OMe
EDC (1.2 equiv)DMAP (1.0 equiv)MeOH (1.2 equiv)
CH2Cl2, 0 °Crt, 2 h
Cl Cl
N
O
OMe
Cl
Cbz
benzyl chloroformate(1.0 equiv)
NaH (1.5 equiv)THF, 0 °Crt, 16 h
1b
220
121.6 (C), 127.3 (C), 128.75 (CH), 128.84 (CH), 128.95 (CH), 129.3 (C), 131.5 (C),
134.2 (C), 135.8 (C), 150.3 (C), 161.9 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C18H14O4NClNa, 366.05036; found, 366.05086.
Preparation of 1‐benzyl 2‐methyl 5‐bromo‐1H‐indole‐1,2‐dicarboxylate (1c).
1c was prepared from the corresponding indole‐2‐carboxylic acid
according to the procedure described above. 1H NMR (392 MHz, CDCl3, ):
3.72 (s, 3H), 5.41 (s, 2H), 7.04 (s, 1H), 7.35 7.54 (m, 6H), 7.74 (d, J = 1.8 Hz,
1H), 7.96 (d, J = 9.0 Hz, 1H). 13C NMR (99 MHz, CDCl3, ): 52.5 ( CH3), 69.9
(CH2), 114.1 (CH), 116.5 (CH), 116.9 (C), 124.7 (CH), 128.7 (CH), 128.8 (CH),
128.9 (CH), 129.2 (C), 129.9 (CH), 131.3 (C), 134.1 (C), 136.1 (C), 150.3 (C), 161.8
(C). HRMS–ESI (m/z): [M+Na]+ calcd for C18H14O4NBrNa, 409.99984; found,
410.00044.
Preparation of 1‐benzyl 2‐methyl 5‐fluoro‐1H‐indole‐1,2‐dicarboxylate (1d).
1d was prepared from the corresponding indole‐2‐carboxylic acid
according to the procedure described above. 1H NMR (392 MHz, CDCl3, ):
3.73 (s, 3H), 5.42 (s, 2H), 7.07 (d, J = 0.7 Hz, 1H), 7.15 (td, J = 2.6, 9.1 Hz, 1H),
7.26 (dd, J = 2.5, 8.1 Hz, 1H), 7.36 7.49 (m, 5H), 8.05 (q, J = 4.5 Hz, 1H). 13C
NMR (99 MHz, CDCl3, ): 52.4 ( CH3), 69.8 (CH2), 107.3 (C F, d, J = 23.5 Hz,
CH), 114.7 (C F, d, J = 3.8 Hz, CH), 115.0 (C F, d, J = 25.4 Hz, CH), 116.2
(C F, d, J = 8.5 Hz, CH), 128.3 (C F, d, J = 10.3 Hz, C), 128.7 (CH), 128.8 (CH),
128.8 (CH), 131.7 (C), 133.8 (C), 134.2 (C), 150.3 (C), 159.4 (C F, d, J = 240.5
Hz, C), 161.9 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C18H14O4NFNa,
350.07991; found, 350.08011.
Preparation of 1‐benzyl 2‐methyl 5‐methoxy‐1H‐indole‐1,2‐dicarboxylate
N
O
OMeCbz
Br
1c
N
O
OMeCbz
F
1d
221
(1e).
1e was prepared from the corresponding indole‐2‐carboxylic acid
according to the procedure described above. 1H NMR (392 MHz, CDCl3, ):
3.73 (s, 3H), 3.86 (s, 3H), 5.41 (s, 2H), 7.00 7.08 (m, 3H), 7.35 7.50 (m, 5H),
7.95 8.01 (m, 1H). 13C NMR (99 MHz, CDCl3, ): 52.3 ( CH3), 55.6 (CH3), 69.5
(CH2), 103.7 (CH), 115.4 (CH), 115.9 (CH), 116.5 (CH), 128.3 (C), 128.6 (CH),
128.7 (CH), 130.7 (C), 132.3 (C), 134.4 (C), 150.6 (C), 156.4 (C), 162.1 (C).
HRMS–ESI (m/z): [M+Na]+ calcd for C19H17O5NNa, 362.09989; found,
362.10004.
Preparation of 1‐benzyl 2‐methyl 6‐bromo‐1H‐indole‐1,2‐dicarboxylate (1f).
1f was prepared from the corresponding indole‐2‐carboxylic acid
according to the procedure described above. 1H NMR (392 MHz, CDCl3, ):
3.72 (s, 3H), 5.42 (s, 2H), 7.08 (s, 1H), 7.36 7.50 (m, 7H), 8.30 (t, J = 0.9 Hz,
1H). 13C NMR (98.5 MHz, CDCl3, ): 52.3 ( CH3), 69.9 (CH2), 115.0 (CH), 118.1
(CH), 120.8 (CH), 123.2 (CH), 126.3 (C), 127.0 (CH), 128.6 (CH), 128.7 (CH),
128.8 (CH), 130.5 (C), 134.1 (C), 138.0 (C), 150.1 (C), 161.7 (C). HRMS–ESI
(m/z): [M+Na]+ calcd for C18H14O4NBrNa, 409.99984; found, 410.00007.
Preparation of 1‐benzyl 2‐methyl 6‐methoxy‐1H‐indole‐1,2‐dicarboxylate
(1g).
1g was prepared from the corresponding indole‐2‐carboxylic acid
according to the procedure described above. 1H NMR (392 MHz, CDCl3, ):
3.73 (s, 3H), 3.79 (s, 3H), 5.41 (s, 2H), 6.89 (dd, J = 2.2, 8.6 Hz, 1H), 7.12 (s, 1H),
N
O
OMeCbz
MeO
1e
N
O
OMeCbz
Br
1f
N
O
OMeCbz
MeO
1g
222
7.33 7.50 (m, 6H), 7.57 (d, J = 2.2 Hz, 1H). 13C NMR (99 MHz, CDCl3, ):
52.1 (CH3), 55.5 (CH3), 69.6 (CH2), 98.1 (CH), 113.9 (CH), 116.7 (CH), 121.1 (C),
122.9 (CH), 128.7 (CH), 128.78 (CH), 128.79 (CH), 128.9 (C), 134.5 (C), 139.3 (C),
150.9 (C), 159.9 (C), 161.9 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C19H17O5NNa, 362.09989; found, 362.09976.
Preparation of 1‐benzyl 2‐methyl 6‐phenyl‐1H‐indole‐1,2‐dicarboxylate
(1h).
Pd(PPh3)4 (231.1 mg, 0.20 mmol) and phenyl boronic acid (487.7 mg, 4.0
mmol) and Na2CO3 (424.0 mg, 4.0 mmol) and 1f (776.4 mg, 2.0 mmol) was
placed in a round bottom flask. Dry toluene (6.0 mL) and a mixture solvent
of MeOH/H2O (1:1, 4.0 mL) were added to the flask at room temperature. The
reaction mixture was stirred at 80 ºC for 6 h. After the reaction mixture was
cooled to room temperature, the mixture was quenched by saturated
NaHCO3 aq. and extracted with EtOAc three times. The combined organic
layer was then dried over MgSO4. The crude material was purified by flash
column chromatography (SiO2, ethyl acetate/hexane, 0:100–10:90) and gel
permeation chromatography (eluent: CHCl3) to give the corresponding
coupling product 1h (358.1 mg, 0.93 mmol, 46%) as a green colored oil. 1H
NMR (395 MHz, CDCl3, δ): 3.76 (s, 3H), 5.43 (s, 2H), 7.16 (d, J = 0.79 Hz, 1 H),
7.33–7.66 (m, 12 H), 8.30 (t, J = 0.99 Hz, 1H). 13C NMR (99 MHz, CDCl3, δ):
52.2 (CH3), 69.7 (CH2), 113.4 (CH), 115.6 (CH), 122.4 (CH), 123.1 (CH), 126.7
(C) 127.29 (CH), 127.33 (CH), 128.6 (CH), 128.7 (CH), 128.75 (CH), 128.78 (CH),
130.6 (C), 134.3 (C), 138.2 (C), 140.3 (C), 140.9 (C), 150.5 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C24H19O4NNa, 408.12063; found, 408.12064.
Preparation of 1‐benzyl 2‐ethyl 1H‐indole‐1,2‐dicarboxylate (1i).
N
O
CbzBr
10 mol % Pd(PPh3)4
B(OH)2
Na2CO3, MeOH/H2Otoluene, 80 ºC, 6 h
N
O
CbzPh
1h
OMe OMe
1f
223
1i was prepared from the corresponding ethyl indole‐2‐carboxylate by the
same Cbz‐protection procedure described above. 1H NMR (392 MHz, CDCl3,
): 1.26 (t, J = 7.2 Hz, 3H), 4.21 (q, J = 7.1 Hz, 2H), 5.41 (s, 2H), 7.12 (s, 1H),
7.26 (t, J = 7.7 Hz, 1H), 7.32 7.49 (m, 6H), 7.59 (d, J = 7.9 Hz, 1H), 8.07 (d, J =
8.6 Hz, 1H). 13C NMR (99 MHz, CDCl3, ): 13.6 ( CH3), 61.0 (CH2), 69.1 (CH2),
114.5 (CH), 114.9 (CH), 121.8 (CH), 123.2 (CH), 126.5 (CH), 127.2 (C), 128.17
(CH), 128.19 (CH), 128.24 (CH), 130.3 (C), 134.1 (C), 137.4 (C), 150.2 (C), 161.2
(C). HRMS–ESI (m/z): [M+Na]+ calcd for C19H17O4NNa, 346.10498; found,
346.10494.
Preparation of 1‐benzyl 2‐isopropyl 1H‐indole‐1,2‐dicarboxylate (1j).
The Mitsunobu reaction was performed according to the literature
procedure.23 In a vacuum dried 100 mL round bottomed flask,
indole‐2‐carboxylate (1.94 g, 12.0 mmol) and triphenylphosphine (3.14 g, 12.0
mmol), 2‐PrOH (764.6 L, 10.0 mmol) were dissolved in dry THF (20.0 mL),
and the mixture was cooled to 0 °C under nitrogen atmosphere. Diisopropyl
azodicarboxylate (2.36 mL, 12.0 mmol) was then added dropwise. After
stirred for 42 h at room temperature, the reaction mixture was passed through
a short silica gel column eluting with Et2O/CH2Cl2. The crude mixture was
purified by flash column chromatography (SiO2, ethyl acetate/hexane, 1:99–
7:93) to obtain the corresponding isopropyl ester (1.70 g, 8.4 mmol, 84%) as a
N
O
OEtCbz
1i
NH
O
ONH
O
OH
i-PrOH (1.0 equiv)PPh3 (1.2 equiv)DIAD (1.2 equiv)
THF, 0 °Crt, 42 h
N
O
O
benzyl-chloroformate(1.2 equiv)
NaH (1.5 equiv)THF, 0 °Crt 4.5 h
Cbz
1.2 equiv
1j
224
white solid.
In a 100 mL round bottomed flask, NaH (302.4 mg, 7.5 mmol) was
dissolved in dry THF (10.0 mL) and the mixture was cooled to 0 °C. The
isopropyl ester (1.02 g, 5.0 mmol) was added in three separate times. Benzyl
chloroformate (856.5 L, 6.0 mmol) was then added dropwise. After stirred
for 4.5 h at room temperature, the reaction mixture was quenched by addition
of water and extracted with CH2Cl2 three times. The combined organic layer
was then dried over MgSO4. After filtration, the solvents were removed by
evaporation. The crude product was purified by flash column
chromatography (SiO2, ethyl acetate/hexane, 3:97–7:93) to obtain 1j (1.61 g, 4.8
mmol, 96%) as a white solid. 1H NMR (392 MHz, CDCl3, ): 1.28 (d, J = 6.4
Hz, 6H), 5.15 (sep, J = 6.2 Hz, 1H), 5.42 (s, 2H), 7.11 (s, 1H), 7.21 7.49 (m, 7H),
7.59 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H). 13C NMR (99 MHz, CDCl3, ):
21.6 (CH3), 69.1 (CH), 69.4 (CH2), 114.9 (CH), 115.2 (CH), 122.1 (CH), 123.5
(CH), 126.8 (CH), 127.6 (C), 128.48 (CH), 128.53 (CH), 128.57 (CH), 131.1 (C),
134.5 (C), 137.5 (C), 150.6 (C), 161.1 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C20H19O4NNa, 360.12063; found, 360.12064.
Preparation of 1‐(tert‐butyl) 2‐methyl 1H‐indole‐1,2‐dicarboxylate (1k).
The Boc‐protection was performed according to the literature procedure.24
In a 100 mL round bottomed flask, methyl indole‐2‐carboxylate (1.76 g, 10.0
mmol) and 4‐dimethylaminopyridine (61.1 mg, 0.50 mmol) were dissolved in
dry MeCN (10.0 mL) under nitrogen atmosphere. Di‐tert‐butyl dicarbonate
(2.53 mL, 11.0 mmol) was then added dropwise. After stirred for 46 h at room
temperature, the reaction mixture was quenched by addition of water and
extracted with CH2Cl2 three times. The combined organic layer was then
dried over MgSO4. After filtration, the solvents were removed by evaporation.
The crude product was purified by flash column chromatography (SiO2, ethyl
acetate/hexane, 0:100–6:94) to obtain 1k (2.66 g, 9.7 mmol, 97%) as a white
solid.1H NMR (392 MHz, CDCl3, ): 1.63 (s, 9H), 3.92 (s, 3H), 7.10 (s, 1H),
7.26 (ddd, J = 1.0, 7.2, 8.0 Hz, 1H), 7.41 (ddd, J = 1.3, 7.1, 9.3 Hz, 1H), 7.60 (d, J
NH
O
OMe N
O
OMe
(Boc)2O (1.1 equiv)DMAP (5 mol %)
MeCN, rt, 46 hBoc
1k
225
= 7.9 Hz, 1H), 8.09 (dd, J = 0.7, 8.2 Hz, 1H). 13C NMR (99 MHz, CDCl3, ):
27.8 (CH3), 52.3 (CH3), 84.6 (C), 114.8 (CH), 122.1 (CH), 123.3 (CH), 126.8 (CH),
127.5 (C), 130.4 (C), 137.8 (C), 149.2 (C), 162.3 (C). HRMS–ESI (m/z): [M+Na]+
calcd for C15H17O4NNa, 298.10498; found, 298.10517.
Determination of Diastereomeric Ratio Values
Diastereomeric ratio values of the borylation products were determined
by 1H NMR analysis of the crude reaction mixture (Figure S1). In the case of
1a, the use of achiral Xantphos ligand and MeOH as a proton source
provided a poor diastereoselectivity (65:35, Figure S1a). In contrast, the
reaction using (R,R)‐L1 and t‐BuOH resulted in a high diastereoselectivity
(97:3, Figure S1b). Diastereomeric ratio values of other borylation products
were determined in the similar way. The minor diastereomer could be
completely separated by silica gel column chromatography because their Rf
values are different enough for separation.
Figure S1. Determination of diastereomeric ratio values by crude 1H NMR.
a) b)
Borylation Product Characterization
Ligand: Xantphos Proton source: MeOH d.r. 65:35
Ligand: (R,R)-L1 Proton source: t-BuOH d.r. 97:3
226
1H and 13C NMR spectra for all borylation products contain
conformational isomers, which is caused by the restricted C–N bond rotation
around the carbamate group.
Borylation Product Characterization
1H and 13C NMR spectra for all borylation products contain
conformational isomers, which is caused by the restricted C–N bond rotation
around the carbamate group.
(S,R)‐1‐Benzyl 2‐methyl
3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐
dicarboxylate [(S,R)‐3a].
1H NMR (392 MHz, CDCl3, δ): 1.27 (s, 12H), 3.35 (d, J = 11.5 Hz, 1H), 3.53
and 3.71 (a pair of s, 3H), 5.08–5.41 (m, 3H), 6.97 (t, J = 7.4 Hz, 1H), 7.11–7.23
(m, 2H), 7.25–7.51 (m, 5H), 7.90 (d, J = 7.9 Hz, 1H). 13C NMR (99 MHz, CDCl3,
): 24.6 ( CH3), 24.9 (CH3), 29.0 (br, BCH), 52.0 and 52.1 (a pair of s, CH3),
62.7 and 62.9 (a pair of s, CH), 67.1 and 67.9 (a pair of s, CH2), 84.2 (C), 114.6
and 114.8 (a pair of s, CH), 122.9 and 123.0 (a pair of s, CH), 124.1 and 124.5 (a
pair of s, CH), 127.3 (CH), 127.9 (CH), 128.1 (CH), 128.4 (CH), 130.6 (C), 135.9
(C), 142.0 (C), 152.0 (C), 171.3 and 171.5 (a pair of s, C). HRMS–ESI (m/z):
[M+Na]+ calcd for C24H28O6N10BNa, 459.19382; found, 459.19421. [α]D22.1 +19.94
(c 1.6 in CHCl3, 93% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 2/98,
0.5 mL/min, 40 °C, (S,R)‐isomer: tR = 33.65 min., (R,S)‐isomer: tR = 29.23 min.
(S,R)‐1‐Benzyl 2‐methyl
5‐chloro‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐dicarbo
N
O
OMeCbz
B OO
(S,R)-3a
227
xylate [(S,R)‐3b].
1H NMR (392 MHz, CDCl3, δ): 1.26 and 1.28 (a pair of s, 12H), 3.30 (d, J =
11.5 Hz, 1H), 3.53 and 3.71 (a pair of s, 3H), 5.05–5.40 (m, 3H), 7.01–7.20 (m,
2H), 7.24–7.47 (m, 5H), 7.81 (d, J = 8.3 Hz, 1H). 13C NMR (99 MHz, CDCl3, ):
24.6 (CH3), 24.9 (CH3), 29.0 (br, BCH), 52.0 (CH3), 62.9 and 63.2 (a pair of s,
CH), 67.3 (CH2), 83.4 and 84.4 (a pair of s, C), 115.4 and 115.5 (a pair of s, CH),
124.5 (CH), 127.2 (CH), 127.9 (C), 128.0 (CH), 128.2 (CH), 128.5 (CH), 132.7 (C),
135.7 (C), 140.7 (C), 152.0 and 153.0 (a pair of s, C), 171.2 (C). HRMS–ESI
(m/z): [M+Na]+ calcd for C24H27O6N10BClNa, 493.15485; found, 493.15576.
[α]D23.9 +15.77 (c 1.1 in CHCl3, 95% ee). Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 2/98, 0.5 mL/min, 40 °C, (S,R)‐isomer: tR = 29.04 min.,
(R,S)‐isomer: tR = 27.73 min.
(S,R)‐1‐Benzyl 2‐methyl
5‐bromo‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐dicarbo
xylate [(S,R)‐3c].
1H NMR (392 MHz, CDCl3, δ): 1.26 and 1.28 (a pair of s, 12H), 3.31 (d, J =
11.5 Hz, 1H), 3.53 and 3.71 (a pair of s, 3H), 5.00–5.42 (m, 3H), 7.24–7.46 (m,
7H), 7.77 (d, J = 8.2 Hz, 1H). 13C NMR (99 MHz, CDCl3, ): 24.6 ( CH3), 24.8
(CH3), 29.0 (br, BCH), 52.0 and 52.2 (a pair of s, CH3), 62.9 and 63.1 (a pair
of s, CH), 67.3 and 68.2 (a pair of s, CH2), 84.4 (C), 115.4 (C), 115.9 and 116.0 (a
pair of s, CH), 127.3 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 130.1 (CH),
N
O
OMeCbz
B OO
Cl
(S,R)-3b
N
O
OMeCbz
B OO
Br
(S,R)-3c
228
133.0 (C), 135.7 (C), 141.2 (C), 151.9 (C), 171.2 (C). HRMS–ESI (m/z): [M+Na]+
calcd for C24H27O6N10BBrNa, 537.10433; found, 537.10518. [α]D24.5 +7.88 (c 0.9
in CHCl3, 92% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 5/95, 0.5
mL/min, 40 °C, (S,R)‐isomer: tR = 44.15 min., (R,S)‐isomer: tR = 27.31 min.
(S,R)‐1‐Benzyl 2‐methyl
5‐fluoro‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)
indoline‐1,2‐dicarboxylate [(S,R)‐3d].
1H NMR (392 MHz, CDCl3, δ): 1.26 and 1.28 (a pair of s, 12H), 3.31 (d, J =
11.5 Hz, 1H), 3.54 and 3.72 (a pair of s, 3H), 5.10–5.45 (m, 3H), 6.72–6.96 (m,
2H), 7.24–7.48 (m, 5H), 7.82 (q, J = 4.5 Hz, 1H). 13C NMR (99 MHz, CDCl3, ):
24.6 (CH3), 24.8 (CH3), 29.0 (br, BCH), 52.0 and 52.1 (a pair of s, CH3), 63.0
and 63.2 (a pair of s, CH), 67.1 and 68.0 (a pair of s, CH2), 83.4 and 84.3 (a pair
of s, C), 111.8 (C F, d, J = 25.4 Hz, CH), 113.3 (C F, d, J = 23.5 Hz, CH), 115.0
(C F, d, J = 7.5 Hz, CH), 127.9 (CH), 128.1 (CH), 128.4 (CH), 132.5 and 132.6
(a pair of s, C), 135.6 and 135.8 (a pair of s, C), 138.0 (C), 152.0 (C), 158.9 (C F,
d, J = 216.6 Hz, C), 171.3 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C24H27O6N10BFNa, 477.18440; found, 477.18502. [α]D23.0 +36.18 (c 0.9 in CHCl3,
95% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 2/98, 0.5 mL/min,
40 °C, (S,R)‐isomer: tR = 28.21 min., (R,S)‐isomer: tR = 26.16 min.
(S,R)‐1‐Benzyl 2‐methyl
5‐methoxy‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐
N
O
OMeCbz
B OO
F
(S,R)-3d
229
1,2‐dicarboxylate [(S,R)‐3e].
1H NMR (392 MHz, CDCl3, δ): 1.24 and 1.28 (a pair of s, 12H), 3.33 (d, J =
11.5 Hz, 1H), 3.53 and 3.71 (a pair of s, 3H), 3.74 and 3.76 (a pair of s, 3H),
5.05–5.45 (m, 3H), 6.62 and 6.72 (a pair of d, J = 7.9 Hz and 8.6 Hz, 1H), 6.74–
6.78 (m, 1H), 7.28–7.47 (m, 1H), 7.79 (d, J = 8.6 Hz, 1H). 13C NMR (99 MHz,
CDCl3, ): 24.6 ( CH3), 24.8 (CH3), 29.0 (br, BCH), 51.9 and 52.1 (a pair of s,
CH3), 55.4 (CH3), 62.9 and 63.1 (a pair of s, CH), 66.9 and 67.8 (a pair of s,
CH2), 84.2 (C), 111.0 and 111.1 (a pair of s, CH), 111.4 and 111.5 (a pair of s,
CH), 114.8 and 115.1 (a pair of s, CH), 127.8 (CH), 128.0 (CH), 128.4 and 128.5
(a pair of s, CH), 132.1 and 132.9 (a pair of s, C), 134.4 and 135.6 (a pair of s, C),
135.9 and 136.0 (a pair of s, C), 151.9 and 153.2 (a pair of s, C), 155.7 and 155.8
(a pair of s, C), 171.4 and 171.5 (a pair of s, C). HRMS–ESI (m/z): [M+Na]+
calcd for C25H30O7N10BNa, 489.20439; found, 489.20475. [α]D24.8 +30.04 (c 1.3 in
CHCl3, 97% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 5/95, 0.5
mL/min, 40 °C, (S,R)‐isomer: tR = 24.09 min., (R,S)‐isomer: tR = 21.41 min.
(S,R)‐1‐Benzyl 2‐methyl
6‐bromo‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐dicarbo
xylate [(S,R)‐3f].
1H NMR (392 MHz, CDCl3, δ): 1.24 and 1.26 (a pair of s, 12H), 3.26 (d, J =
11.5 Hz, 1H), 3.52 and 3.70 (a pair of s, 3H), 5.05–5.42 (m, 3H), 6.97–7.13 (m,
2H), 7.24–7.48 (m, 5H), 8.08 (s, 1H). 13C NMR (99 MHz, CDCl3, ): 24.6 ( CH3),
N
O
OMeCbz
B OO
MeO
(S,R)-3e
N
O
OMeCbz
B OO
Br
(S,R)-3f
230
24.8 and 24.9 (a pair of s, CH3), 29.0 (br, BCH), 52.0 (CH3), 63.1 and 63.2 (a
pair of s, CH), 67.4 and 68.2 (a pair of s, CH2), 83.4 and 84.3 (a pair of s, C),
117.7 (CH), 120.8 (C), 125.3 (CH), 125.8 (CH), 128.0 (CH), 128.2 (CH), 128.5
(CH), 129.8 (C), 135.7 (C), 143.3 (C), 151.9 (C), 171.1 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C24H27O6N10BBrNa, 537.10433; found, 537.10492. [α]D24.9
+37.06 (c 1.2 in CHCl3, 86% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane
= 3/97, 0.5 mL/min, 40 °C, (S,R)‐isomer: tR = 24.16 min., (R,S)‐isomer: tR = 22.73
min.
(S,R)‐1‐Benzyl 2‐methyl
6‐methoxy‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐
1,2‐dicarboxylate [(S,R)‐3g].
1H NMR (392 MHz, CDCl3, δ): 1.26 (s, 12H), 3.28 (d, J = 11.1 Hz, 1H), 3.53
and 3.62 (a pair of s, 3H), 3.71 and 3.80 (a pair of s, 3H), 5.05–5.40 (m, 3H),
6.43–6.58 (m, 1H), 7.01 (dd, J = 1.1, 8.3 Hz, 1H), 7.05–7.49 (m, 5H), 7.58 (s, 1H). 13C NMR (99 MHz, CDCl3, ): 24.6 ( CH3), 24.8 (CH3), 29.0 (br, BCH), 51.9
(CH3), 55.1 and 55.4 (a pair of s, CH3), 63.5 (CH), 67.0 and 68.1 (a pair of s,
CH2), 84.1 (C), 100.8 and 101.6 (a pair of s, CH), 108.4 and 109.2 (a pair of s,
CH), 122.4 (C), 124.2 and 124.6 (a pair of s, CH), 127.8 (CH), 128.06 and 128.15
(a pair of s, CH), 128.4 (CH), 135.8 (C), 143.1 (C), 152.0 (C), 159.3 and 159.4 (a
pair of s, C), 171.4 and 171.5 (a pair of s, C). HRMS–ESI (m/z): [M+Na]+ calcd
for C25H30O7N10BNa, 489.20439; found, 489.20487. [α]D25.1 +52.91 (c 1.0 in
CHCl3, 93% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 5/95, 0.5
mL/min, 40 °C, (S,R)‐isomer: tR = 24.16 min., (R,S)‐isomer: tR = 21.69 min.
N
O
OMeCbz
B OO
MeO
(S,R)-3g
231
(S,R)‐1‐Benzyl 2‐ethyl
3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐
dicarboxylate [(S,R)‐3h].
1H NMR (392 MHz, CDCl3, δ): 1.29 (s, 12H), 3.39 (d, J = 11.7 Hz, 1H), 3.54
and 3.73 (a pair of s, 3H), 5.14–5.38 (m, 3H), 7.20 (s, 2H), 7.28–7.50 (m, 9H),
7.61 (d, J = 7.7 Hz, 1H), 8.18 (s, 1H). 13C NMR (99 MHz, CDCl3, ): 24.7 ( CH3),
24.9 (CH3), 29.0 (br, BCH), 52.0 and 52.1 (a pair of s, CH), 63.1 (CH3), 67.1
and 68.3 (a pair of s, CH), 84.2 (C), 113.5 and 113.9 (a pair of s, CH), 121.8 and
122.1 (a pair of s, CH), 124.2 and 124.6 (a pair of s, CH) 126.9 and 127.0 (a pair
of s, CH), 127.2 (CH), 127.9 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 129.9 (C),
135.9 (C), 140.7 (C), 141.2 (C), 142.6 (C), 152.1 (C), 171.5 (C). HRMS–ESI (m/z):
[M+Na]+ calcd for C30H32O6N10BNa, 535.22512; found, 535.22522. [α]D25.1 +26.92
(c 1.3 in CHCl3, 88% ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 5/95,
0.5 mL/min, 40 °C, (S,R)‐isomer: tR = 28.32 min., (R,S)‐isomer: tR = 23.75 min.
(S,R)‐1‐Benzyl 2‐ethyl
3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐
dicarboxylate [(S,R)‐3i].
1H NMR (392 MHz, CDCl3, δ): 1.07 (t, J = 7.3 Hz, 3H), 1.27 (s, 12H), 3.34 (d,
J = 11.7 Hz, 1H), 3.95–4.30 (m, 2H), 5.09–5.38 (m, 3H), 6.96 (t, J = 7.5 Hz, 1H),
7.13–7.22 (m, 2H), 7.26–7.52 (m, 5H), 7.89 (d, J = 8.1 Hz, 1H). 13C NMR (99
MHz, CDCl3, ): 13.8 ( CH3), 24.6 (CH3), 24.8 (CH3), 29.0 (br, BCH), 61.1
N
O
OMeCbz
Ph
B OO
(S,R)-3h
N
O
OEtCbz
B OO
(S,R)-3i
232
(CH2), 62.8 and 63.0 (a pair of s, CH), 67.1 and 67.8 (a pair of s, CH2), 84.1 (C),
114.5 and 114.7 (a pair of s, CH), 122.9 (CH), 124.1 and 124.5 (a pair of s, CH),
127.2 (CH), 127.9 (CH), 128.1 (CH), 128.4 (CH), 130.7 (C), 135.9 (C), 142.0 (C),
152.1 (C), 171.1 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C25H30O6N10BNa,
473.20947; found, 473.20937. [α]D24.6 +25.45 (c 1.0 in CHCl3, 95% ee). Daicel
CHIRALPAK® OZ‐3, 2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C,
(S,R)‐isomer: tR = 32.84 min., (R,S)‐isomer: tR = 18.16 min.
(S,R)‐1‐Benzyl 2‐isopropyl
3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐
dicarboxylate [(S,R)‐3j].
1H NMR (392 MHz, CDCl3, δ): 1.03 (d, J = 6.2 Hz, 3H), 1.09 (d, J = 6.6 Hz,
3H), 1.28 (s, 12H), 3.31 (d, J = 11.3 Hz, 1H), 4.87 (septet, J = 6.3 Hz, 1H), 5.10 (d,
J = 5.7 Hz, 1H), 5.18 (d, J = 12.8 Hz, 1H), 5.26 (d, J = 12.5 Hz, 1H), 6.97 (t, J = 7.5
Hz, 1H), 7.08–7.20 (m, 2H), 7.28–7.51 (m, 5H), 7.88 (d, J = 8.0 Hz, 1H). 13C
NMR (99 MHz, CDCl3, ): 21.4 (CH3), 21.5 (CH3), 24.6 (CH3), 24.9 (CH3), 29.5
(br, BCH), 63.1 (CH), 67.1 (CH2), 69.1 (CH), 84.1 (C), 114.5 (CH), 122.9 (CH),
124.3 (CH), 127.1 (CH), 127.9 (CH), 128.1 (CH), 128.5 (CH), 131.0 (C), 135.9 (C),
142.0 (C), 152.2 (C), 170.8 (C). HRMS–ESI (m/z): [M+Na]+ calcd for
C26H32O6N10BNa, 487.22512; found, 487.22509. [α]D24.8 +31.90 (c 1.0 in CHCl3,
90% ee). The ee value was determined by HPLC analysis of the
corresponding silyl ether after oxidation, followed by standard silyl
protection with TBSCl of the borylated product in comparison of the racemic
sample. Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 2/98, 0.5 mL/min,
40 °C, (S,R)‐isomer: tR = 12.27 min., (R,S)‐isomer: tR = 25.08 min.
N
O
OCbz
B OO
(S,R)-3j
233
(S,R)‐1‐Benzyl 2‐methyl
3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)indoline‐1,2‐
dicarboxylate [(S,R)‐3k].
1H NMR (392 MHz, CDCl3, δ): 1.27 and 1.28 (a pair of s, 12H), 1.49 and 1.59
(a pair of s, 9H), 3.33 (d, J = 11.5 Hz, 1H), 3.70 and 3.74 (a pair of s, 3H), 5.02
and 5.08 (a pair of d, J = 11.8 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 7.13 and 7.16 (a
pair of d, J = 7.2 Hz and 7.5 Hz, 2H), 7.39–7.91 (m, 1H). 13C NMR (99 MHz,
CDCl3, ): 24.6 ( CH3), 24.8 (CH3), 28.1 (CH3), 29.0 (br, BCH), 51.8 (CH3),
62.5 and 63.0 (a pair of s, CH), 81.0 and 82.1 (a pair of s, C), 84.1 (C), 114.4
(CH), 122.4 (CH), 124.0 and 124.4 (a pair of s, CH), 127.1 (CH), 130.5 (C), 142.3
(C), 151.4 (C), 171.8 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C21H30O6N10BNa,
425.20947; found, 425.20959. [α]D18.6 +38.09 (c 2.3 in CHCl3, 96% ee). The ee
value was determined by HPLC analysis of the corresponding ester after
oxidation, followed by standard esterification with p‐nitrobenzoyl chloride of
the borylated product in comparison of the racemic sample. Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 3/97, 0.5 mL/min, 40 °C,
(S,R)‐isomer: tR = 44.43 min., (R,S)‐isomer: tR = 86.51 min.
Borylation Product Functionalization Procedure
Procedure for the synthesis of chiral 1,2‐aminoalcohol (S,R)‐4 through
the silyl protection following oxidation of (S,R)‐3d.
The oxidation was performed according to the literature procedure.24 In a
reaction vial, (S,R)‐3d (45.5 mg, 0.10 mmol) was dissolved in THF/H2O (1:1, 2
mL). NaBO3•4H2O (61.5 mg, 0.40 mmol) was then added at room
temperature. After stirred for 2 h, the reaction mixture was extracted three
times with EtOAc, dried over MgSO4, and filtered. The resulting crude
material was used in the next reaction without further purification.
N
O
OMeBoc
B OO
(S,R)-3k
234
The crude material and imidazole (20.4 mg, 0.30 mmol) was dissolved in
dry CH2Cl2 (1 mL) under a nitrogen atmosphere. TBS chloride (22.6 mg, 0.15
mmol) was then added at room temperature. After stirred for 4 h, the
reaction mixture was passed through a short silica gel column eluting with
Et2O/CH2Cl2 (50:50). The crude mixture was purified by flash column
chromatography (SiO2, ethyl acetate/hexane, 2:98–6:94) to afford the
corresponding silyl ether (S,R)‐4 (29.5 mg, 0.064 mmol, 64%) as a colorless oil.
(S,R)‐1‐Benzyl 2‐methyl
3‐((tert‐butyldimethylsilyl)oxy)‐5‐fluoroindoline‐1,2‐dicarboxylate
[(S,R)‐4].
1H NMR (392 MHz, CDCl3, δ): 0.17 (s, 3H), 0.24 (s, 3H), 0.92 (s, 9H), 3.52
and 3.73 (a pair of s, 3H), 4.93 (d, J = 9.0 Hz, 1H), 5.10 and 5.31 (a pair of d, J =
11.8 Hz and 12.2 Hz, 2H), 5.62 (d, J = 9.0 Hz, 1H), 6.91 (dd, J = 1.8, 7.9 Hz, 1H),
7.00 (t, J = 8.6 Hz, 1H), 7.20–7.50 (m, 5H), 7.92 (q, J = 4.4 Hz, 1H). 13C NMR (99
MHz, CDCl3, ): 4.8 ( CH3), 18.0 (C), 25.6 (CH3), 52.0 (CH3), 66.6 (CH), 67.4
(CH2), 71.7 (CH), 111.6 (C F, d, J = 25.4 Hz, CH), 115.7 (C F, d, J = 8.5 Hz,
CH), 116.2 (C F, d, J = 24.4 Hz, CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 132.4
and 132.5 (a pair of s, C), 135.7 (C), 137.5 (C), 151.9 (C), 159.2 (C F, d, J =
240.5 Hz, C), 168.1 (C). HRMS–ESI (m/z): [M+Na]+ calcd for C24H30O5NFNaSi,
482.17695; found, 482.17679. [α]D19.2 +54.33 (c 2.8 in CHCl3, 94% ee). Daicel
CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 2/98, 0.5 mL/min, 40 °C,
(S,R)‐isomer: tR = 16.44 min., (R,S)‐isomer: tR = 22.72 min.
N
O
OMeCbz
OTBSF
(S,R)-4
235
Determination of the Absolute Configurations of Borylation Products
The absolute configuration of the product was determined based on X‐ray
crystallographic analysis of the compound (S,R)‐5, which was derived
through the oxidation of borylation product (S,R)‐3c. The absolute
configurations of other borylation products were deduced by this result. The
details were summarized in Figure S2 and Table S1.
Figure S2. ORTEP structure of (S,R)‐5. Thermal ellipsoids are drawn at the
50% probability level.
236
Table S1. Summary of X‐ray crystallographic data for (S,R)‐5.
CCDC Name 1055818
Empirical Formula C17H16BrNO5
Formula Weight 394.22
Crystal System triclinic
Crystal Size / mm
0.176 × 0.097 ×
0.092
a / Å 11.5617(14)
b / Å 14.7143(19)
c / Å 16.4512(18)
β / º 94.165(3)
V / Å3 2522.0(5)
Space Group P1 (#1)
Z value 6
Dcalc / g cm−3 1.557
Temperature / K 123
2θmax / ° 45.0
μ (MoKα) / cm−1 24.783
No. of Reflections
Measured
Total: 15030 Unique: 11291 (Rint = 0.0926)
No. of Observations (All reflections) 11291
Residuals: R1 (I > 2.00(I))
0.0995
Residuals: wR2
(All reflections)0.3270
Goodness of Fit Indicator (GOF)
1.138
Maximum Peak in Final Diff. Map / Å3
1.24 e‐
Minimum Peak in Final Diff. Map / Å3
1.70 e‐
237
We also confirmed the relative configuration of the borylation product
(S,R)‐3a by 1H NMR NOE experiment. The result was shown as below.
Details of DFT Calculations
All calculations were performed with the Gaussian 09W (revision C.01)
program package.25 Geometry optimizations were performed with
B3PW91/cc‐pVDZ in the gas‐phase. The molecular orbitals were drawn by
the GaussView 5.0 program. The frequency calculations were conducted on
gas‐phase optimized geometries to check the all the stationary points as
either minima or transition states.
Theoretical investigation to prove the mechanism of the addition of
borylcopper(I) intermediate to indole‐2‐carboxylate based on HOMO‐LUMO
orbital analysis (B3PW91/cc‐pVDZ) was carried out. According to the
mechanistic investigation reported by Marder, Lin and co‐workers,26
copper(I)‐catalyzed borylation of ,‐unsaturated carbonyl compounds
would proceed via 3,4‐addition pathway because the LUMO of the substrate
is mainly located in the C=C double bond, which can interact with the
HOMO of borylcopper(I) intermediate. Although the current substrate is
aromatic indole‐2‐carboxylate, we found that C2 C3 double bond makes the
higher contribution than that of carbonyl moiety in the LUMO orbitals,
indicating the boryl cupration of the indoles would proceed via 3,4‐addition
pathway in a similar manner to the borylation of ,‐unsaturated carbonyl compounds (Figure S3). Thus, the reactivity for the dearomative borylation
can be discussed by comparison between LUMO of 1a and LUMO+1 of 1o,
which are the most lowest unoccupied orbital around the reactive C2C3 site of the indole structures. As shown in Figure S3, the LUMO level of 1a is
considerably lower than LUMO+1 of 1o, indicating that the
N
B
CO2Me
Cbz
HH
4.5%OO
238
electron‐withdrawing ester group at the 2‐position of indoles facilitate the
addition reaction of borylcopper(I) active species to the indoles.
Figure S3. Orbital Analysis of 1a and 1o.
239
As shown in Figure S4, the HOMO orbitals of borylcopper(I) complex can
effectively overlap with the LUMO orbitals of indole‐2‐carboxylate in the
3,4‐addition pathway. In contrast, the orbital interaction between HOMO of
borylcopper(I) and LUMO of indole‐2‐carboxylate in the 1,4‐addition
pathway would be not favorable because the phase of these orbitals are
unmatched. Thus, these results also suggest that the borylation of
indole‐2‐carboxylate would proceed via 3,4‐addtion pathway.
Figure S4. Orbital Analysis of Borylcopper(I) Complex and 1a
Figure S5. Optimized Structures (I, III, TS, IV) with Structural Parameters
and Free (in parentheses) and Electronic (in bracket) Energies in Figure 3b.
B CuP
P
O
O
N OMe
O
Cbz
3,4-addition pathway 1,4-addition pathway
disfavored(the MO phase is unmatched)
favored(the MO phase is matched)
LUMO
HOMO B CuP
P
O
O
N OMe
O
Cbz
small contributionon LUMO
240
References
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2. For a review concerning the application of dearomatization strategies to
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8. A. S. Dudnik, V. L. Weidner, A. Motta, M. Delferro, T. J. Marks, Nat.
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9. For a report concerning the palladium‐catalyzed non‐enantioselective
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10. For a report concerning an organocatalytic N B bond ‐forming
dearomatization, see: T. Ohmura, Y. Morimasa, M. Suginome, J. Am.
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11. For selected examples of copper(I)‐catalyzed enantioselective borylation
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Sawamura, J. Am. Chem. Soc. 2007, 129, 14856 14857; b) Y. Sasaki, C.
Zhong, M. Sawamura, H. Ito, J. Am. Chem. Soc. 2010, 132, 1226 1227; c)
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Yamamoto, Y. Takenouchi, T. Ozaki, T. Miya, H. Ito, J. Am. Chem. Soc.
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Sadighi, Organometallics 2006, 25, 2405–2408; b) L. Dang, H. Zhao, Z. Lin,
T. B. Marder, Organometallics 2007, 26, 2824–2832; c) L. Dang, Z. Lin, T. B.
Marder, Organometallics 2008, 27, 4443–4454; d) K. Kubota, E. Yamamoto,
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1522; b) J. L. Pinder, S. M. Weinreb, Tetrahedron Lett. 2003, 44, 4141–4143;
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3975–3984; b) W. Zi, Z. Zuo, D. Ma, Acc. Chem. Res. 2015, 48, 702–711.
15. Diastereomeric ratio values of the products were determined by 1H NMR
analysis of the crude reaction mixture. The minor diastereomer could be
completely separated by silica gel column chromatography. The ee
values were determined by HPLC analysis of the isolated products. The
configuration of the borylation product was determined by NOE analysis
of (S,R)‐3a and X‐ray crystallographic analysis of the compound (S,R)‐5,
242
which has been provided in Figure 2. The details have been provided in
the Supporting Information.
16. A method has been developed for the organocatalytic enantioselective
oxidation of indoles using a directing group, see: F. Kolundzic, M. N.
Noshi, M. Tjandra, M. Movassaghi, S. Miller, J. Am. Chem. Soc. 2011, 133,
9104–9111.
17. 2‐Methyl indole was selected as a substrate to avoid deprotonation at the
2‐position by Na(O‐t‐Bu). We also confirmed that the borylation of
non‐substituted Cbz‐protected indole resulted in no reaction.
18. The details of the DFT calculation have been provided in the Supporting
Information.
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244
Chapter 7.
Copper(I)‐Catalyzed Regio‐ and Enantioselective
Borylation of 1,2‐Dihydropyridines
245
Abstract
The author reports a novel approach to chiral 3‐borylpiperidines via the
copper(I)‐catalyzed unprecedented regio‐ , diastereo‐ and enantioselective
protoborylation of 1,2‐dihydropyridines derived from partial reduction of
pyridine derivatives. This dearomatization/enantioselective borylation
sequence of cheap and readily available aromatic compound pyridines
provides simple, mild and rapid access to a variety of chiral piperidines in
combination with the stereospecific transformation of a stereogenic CB
bond. Theoretical study of the reaction mechanism has also been described.
Introduction
Chiral piperidines are very important components in a wide variety of
naturally occurring bioactive molecules and pharmaceutical drugs.1 Despite
significant progress in synthetic approaches toward these type of molecules,
the development of a simple, mild, and direct method for their preparation is
still in great demand. Considering the abundance of readily available
aromatic compounds, enantioselective dearomatization reaction of pyridine
derivatives is the most efficient and powerful transformation as they can be
used to provide a direct route to a variety of saturated chiral nitrogen
containing six membered ring systems.2,3 Over the last decades, several
strategies involving nucleophilic addition to a pyridinium salt or stepwise
reduction/enantioselective catalysis for the dearomatization of pyridines
have been developed.3,4
Recently, Ito group reported the first CB bond forming
enantioselective dearomatization of N‐heteroaromatic compounds, indoles,
in the presence of copper(I) catalysis to give the chiral 3‐boryl‐indolines with
excellent regio‐, diastereo‐ and enantioselectivity.5‐7 This type of
transformation has great potential in synthetic and medicinal applications
because chiral N‐heterocyclic organoborons are amenable to various
stereospecific functionalization of a stereogenic CB bond.8,9 Accordingly, his attention was then attracted to the enantioselective preparation of chiral
boryl‐piperidines through dearomatization of pyridines, which can be
employed as a novel nucleophile for the synthesis of piperidine‐based
246
bioactive compounds.9 Initial effort has been focused on the development of
a direct CB bond forming dearomatization of N‐acyl pyridinium salts using
copper(I) catalysis. Although the 1,2‐borylation proceeded, the author failed
to isolate the product due to its significant instability toward the purification.
Thus, the author turned his attention to the development of an alternative
stepwise strategy that combines Fowler’s dearomative reduction of
pyridines10 and subsequent copper(I)‐catalyzed enantioselective borylation of
resulting unstable 1,2‐dihydropyridines.4 However, this novel method has
significant difficulty in the control of regioselectivity as well as diastereo‐
and enantioselectivity for nitrogen containing conjugated diene substrates,
which has been no reports on selective borylation reaction of such type of
compounds in the literature.11 Herein the author reports an enantioselective
synthesis of chiral 3‐boryl‐tetrahydropyridines via the chiral
diphosphine/copper(I)‐catalyzed unprecedented regio‐, diastereo‐ and
enantioselective protoborylation of 1,2‐dihydropyridines derived from
dearomative reduction of readily available pyridine derivatives (Scheme 1a).
This stepwise reduction/borylation strategy would have great utility in
medicinal chemistry and drug discovery because further derivatization using
the boryl group as well as the remaining enamine moiety easily leads to
chiral piperidines bearing a C 3 stereocenter that are important components
in various pharmaceutical drugs (Scheme 1b).1
247
Scheme 1. (a) Dearomatization/Enantioselective Borylation Stepwise Strategy.
(b) Representative Chiral piperidine‐based Bioactive Compounds.
Results and Discussion
The results of an extensive series of optimization experiments revealed that
the reaction of methoxycarbonyl‐protected 1,2‐dihydropyridines 2a, which
was prepared through the Fowler’s NaBH4 reduction of pyridine (1a), with
bis(pinacolato)diboron (3) (1.2 equiv) in the presence of CuCl/(R,R)‐QuinoxP*
(5 mol %), K(O‐t‐Bu) (20 mol %) and MeOH (2.0 equiv) in THF at 10 °C
afforded the desired chiral 3‐borylpiperidine (R)‐4a in high yield (93%) with
excellent enantioselectivity (99% ee) (Table 1, entry 1). In this reaction
conditions, other regioisomers were not detected by 1H NMR analysis of the
crude reaction mixture. The use of (R,R)‐BenzP* and (R,R)‐Me‐Duphos also
provided high enantioselectivities (Table 1, entries 2 and 3, 98% ee and 93%
ee, respectively). No product was observed when triarylphosphine type
ligand such as (R)‐BINAP and (R)‐SEGPHOS ligand were used for the
KDM2A inhibitor
()-preclamol
HN
F
O
O
O
()-paroxetine
NON
N
ibrutinib
NO
zamifenacineO
O
Ph
Ph
N OH
NN
Ph
O
N N N
CO2H
N
NNH2
OPh
cat. Cu/L*B2(pin)2
alcoholN
R3
R1
B(pin)
R2
pyridines conjugated diene
N
R1 R2
N
R1 R2
R3R3-X
hydridesource
b) Representative chiral piperidine-based bioactive molecules
a) Dearomatization/enantioselective borylation sequence (This work)
cheapabundant
borylpiperidineshighly regio-, stereoselectivenovel chiral building block
difficult to control regio-and stereoselectivity
248
reaction (Table 1, entries 4 and 5). Other chiral ligands including (R,R)‐BDPP
and (R,S)‐Josiphos also provided the borylation product, but the
enantioselectivities were poor (Table 1, entried 6 and 7, 55% ee and 73% ee,
respectively). The nature of the proton source was also important to the
reactivity and enantioselectivity observed during the transformation (Table 1,
entries 8 and 9). The use of sterically hindered i‐PrOH instead of MeOH
resulted in a low enantioselectivity (Table 1, entry 8, 79% ee). Furthermore,
the reaction using PhOH provided a low yield and enantioselectivity (Table 1,
entry 9, 40%, 55% ee). Increasing the reaction temperature slightly decreased
the enantioselectivity (Table 1, entry 10, 93% ee). Notably, the reaction on 5.0
mmol scale proceeded to give the product at gram scale with excellent
enantioselectivity (Table 1, entry 11, 99% ee). This enantioselective borylation
also proceeded with 1 mol % copper(I) catalyst and showed high
enantioselectivity (99% ee), while longer reaction time was required for the
completion of the reaction (Table 1, entry 12).
249
Table 1. Reaction Optimiazation Study
entry chiral ligand NMR yield (%)
1
2
3
4
5
6
7
8
9
10
11c
12d,e
93
92
82
<5
<5
97
20
92
40
92
96
91
(R,R)-QuinoxP*
(R,R)-BenzP*
(R,R)-Me-Duphos
(R)-BINAP
(R)-SEGPHOS
(R,R)-BDPP
(R,S)-Josiphos
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
(R,R)-QuinoxP*
alcohol
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
t-BuOH
PhOH
MeOH
MeOH
MeOH
ee (%)b
99
98
93
55
73
79
55
93
99
99
aConditions: CuCl (0.025 mmol), ligand (0.025 mmol), 2a (0.5 mmol), bis(pinacolato)diboron (2) (0.6 mmol) and K(O-t-Bu) (0.1 mmol) in THF (1.0 mL). bThe ee values for 3a were determined by HPLC analysis. cThe reaction was cariied out at 5.0 mmol scale. dThe reaction was carried out with 1 mol % copper(I) catalyst and the reaction time was 16 h.
CuCl (5 mol %)chiral ligand (5 mol %)B2(pin)2 (1.2 equiv) (3)
K(O-t-Bu) (20 mol %)MeOH (2 equiv)THF, temp., 2-4 h2a (R)-4a
NaBH4ClCO2Me
MeOH78 C1 h, 71%1a
NNO
MeO
NO
MeO
B(pin)
temp. (C)
10
10
10
10
10
10
10
10
10
30
10
10
P
P
Me tBu
tBu Me
(R,R)-BenzP*
N
N P
P
Me tBu
tBu Me
(R,R)-QuinoxP*
O
O
O
O
PPh2
PPh2
(R)-SEGPHOS
P
PMeMe
Me
Me
(R,R)-Me-Duphos (R,R)-BDPP
PP
PPh2
PPh2
(R)-SEGPHOS
FeP
P
(R,S)-Josiphos
250
Next, the author proceeded to investigate the diastereo‐ and
enantioselective borylation process using 4‐phenylpyridine (2b) as a
substrate (Scheme 2). The 1,2‐dihydropyridine 2b was successfully obtained
in good yield (81%) through the dearomative reduction of 1b. Unfortunately,
however, the subsequent enantioselective borylation of 2b under the
optimized reaction conditions proceeded with a significantly low
enantioselectivity (39% ee) even though the regio‐ and diastereoselectivities
were excellent (d.r. 99:1). Thus, the reaction optimization using 2b as a
substrate was carried out again (See SI). As a result, it was found that the use
of (R)‐SEGPHOS chiral ligand and t‐BuOH in toluene/DME/THF co‐solvent
system gave the desired chiral 3‐borylpiperidine bearing consecutive
stereogenic centers (R,R)‐4b in good yield (94%) with high diastereo‐ and
enantioselectivities (d.r. 97:3, 93% ee).12,13 The anti configuration of (R,R)‐4b
was confirmed by NOE analysis.
Scheme 2. Regio‐ and Diastereo‐ and Enantioselective Borylation of
4‐Phenyl‐1,2‐Dihydropyridine (2b)
With an optimized procedure in hand, the author proceeded to investigate
the scope of the reaction using a variety of pyridine substrates (Table 2). The
reaction of 1,2‐dihydropyridines bearing various carbamate type protecting
groups (2a, 2c‐2g) in the presence of copper(I)/(R,R)‐QuinoxP* catalyst
proceeded well to give the desired products [(R)‐4a, (R)‐4c g ] in
good yields with high enantioselectivities (Table 2,
76 93 ee). The 5 ‐substituted 1,2‐dipydropyridines (2h
and 2i) were also borylated to afford the chiral 3‐borylpiperidines [(R)‐4h
and (R)‐4i] with excellent enantioselectivities without other undesirable
regioisomers (Table 2, 86%, 92% ee and 67%, 96% ee, respectively). The
copper(I)/(R)‐SEGPHOS complex catalyzed enantioselective borylation of
CuCl (5 mol %)ligand (5 mol %)3 (1.2 equiv)
K(O-t-Bu) alcohol
(R,R)-QuinoxP*, MeOH, THF, 0 C: 91%, d.r. 99:1, 39% ee
(R)-SEGPHOS, t-BuOH, toluene/DME/THF, 0 C: 94%, d.r. 97:3, 93% ee
2b (R,R)-4b
NaBH4ClCO2Me
MeOH78 C1 h, 81%1b
NNO
MeO
NO
MeO
B(pin)
PhPh Ph
251
various 4‐aryl 1,2‐dihydropyridines (2b, 2j2l) provided the corresponding
products bearing consecutive stereogenic centers with high diastereo‐ and
enantioselectivities (d.r. 94:6 98:2, 93 ee). However, the reactions of
4‐(3‐bromophenyl) 1,2‐dihydropyridine (2m) and
4‐(3‐trifluoromethylphenyl) 1,2‐dihydropyridine (2n) in the presence of
copper(I)/(R)‐SEGPHOS catalyst resulted in low yields (<10%). Fortunately,
the author found that the use of (R,R)‐BDPP allowed to synthesize the
corresponding products [(R,R)‐4m and (R,R)‐4n], but the enantioselectivities
were moderate (74% ee and 66% ee, respectively). The present catalytic
system could not be applied to the 3‐subsstituted 1,2‐dihydropyridines 2o.
252
Table 2. Substrate Scope
91%, d.r. 97:396% ee
(R)-4a
90%, 99% ee
(R,R)-4m93%, d.r. 90:1074% ee
NaBH4 orLiBH4
ClCO2R3
MeOH78 C
cat. Cu / L*B2(pin)2 (3)
K(O-t-Bu)alcohol
1 2
N
R1 R2
N
R1 R2
R3O
O N
R1 R2
R3O
OB(pin)
(R)-4, or (R,R)-4
N
MeO
OB(pin)
(R)-4c88%, 98% ee
N
O
OB(pin)
(R)-4d90%, 97% ee
N
O
OB(pin)
(R)-4e76%, 97% ee
N
BnO
OB(pin)
(R)-4f84%, 93% ee
N
PhO
OB(pin) N
O
OB(pin)
(R)-4g91%, 97% ee
(R)-4h86%, 92% ee
N
MeO
OB(pin)
Me
(R)-4i67%, 96% ee
N
MeO
OB(pin)
Me
(R,R)-4b90%, d.r. 94:693% ee
N
MeO
OB(pin)
Ph
N
MeO
OB(pin)
Me
N
MeO
OB(pin)
F
N
MeO
OB(pin)
OMe
(R,R)-4j91%, d.r. 98:295% ee
(R,R)-4k82%, d.r. 96:496% ee
(S,S)-4l
N
MeO
OB(pin)
Br
(R,R)-4n79%, d.r. 87:1366% ee
N
MeO
OB(pin)
CF3
no reaction
N
MeO
OB(pin)
Me
(R)-4o
253
Enantioenriched chiral 3‐boryl‐tetrahydropyridines could potentially be
used as building blocks through the stereospecific functionalization of a
stereogenic CB bond. For examples, the obtained borylation product (R)‐4a
was subjected to NaBO3 oxidation, followed by the acylation and reduction
of an enamine moiety to afford the chiral piperidinol (R)‐5 with high
enantiomeric excess (Scheme 3). Furthermore, the Aggarwal’s
cross‐coupling14 of (R)‐6, which was prepared by reduction of (R)‐4a, with
(3‐methoxyphenyl)lithium afforded the ()‐preclamol precursor (S)‐7 with
excellent stereospecificity (Scheme 3).
Scheme 3. Stereospecific Functionalization of Borylation Product (R)‐4a
To demonstrate the practical usefulness of this methodology in the
selective synthesis of natural products and pharmaceutical drugs, the author
applied the obtained product (S,S)‐4l to the preparation of antidepressant
drug ()‐proxetine (R,S)‐10 (Scheme 4).8c,15 The boryl group in the product
(R,R)‐4r was functionalized through the one carbon homologation16 and
subsequent oxidation, mesyl protection to lead the corresponding mesylate
(R,S)‐8, which was then subjected to the Williamson esterification,
hydrogenation of an alkene moiety with Pd/C to form (R,S)‐9 with high
enantiomeric purity (94% ee). Finally, the deprotection of a methyl carbamate
moiety with KOH provided ()‐paroxetine (R,S)‐10. Spectroscopic and optical rotation data matched literature values. The author envisions that
1. NaBO34H2O2. (PhCO)2O, pyridine DMAP, CH2Cl2
3. Pd/C, H2 THF/MeOH
Pd/C, H2THF/MeOH
(R)-696%
Li OMe
1. (1.2 equiv)
2. NBS, MeOH, 78 C
(R)-4a99% ee
N
MeO
OO
O
(R)-577%, 98% ee
N
MeO
OB(pin)
N
MeO
O OMe
(S)-751%, 98% ee
( )-preclamol precursor
N
MeO
OB(pin)
254
these type of novel chiral boronates will find further application for efficient
preparation of piperidine‐based bioactive molecules.
Scheme 4. Synthesis of ()‐Paroxetine
To prove the reaction mechanism, the author conducted a deuterium
labeling experiment (Scheme 5). The borylation of 2e using MeOD instead of
MeOH under optimized conditions gave the 4‐position labeled product
((R)‐4e’, D >95%) with high enantioselectivity (98% ee). The syn configuration
between a boryl group and deuterium atom was confirmed by NOE analysis.
These results suggest that the current borylation proceeds through the regio‐
and enantioselective syn‐4,3‐addition of a borylcopper(I) active species to
1,2‐dihydropyridines, followed by stereoretentive SE2 protonation of the
allylcopper(I) intermediate by an alcohol additive.17
Scheme 5. Deuterium Labeling Experiment
( )-paroxetineantidepressant drug
(R,S)-1061%
d.r. 97:396% ee
(S,S)-4l
3. MsCl, Et3N
1. LiCH2Cl,78 C2. NaBO34H2O
(R,S)-884% (3 steps), d.r. 97:3
N
MeO
O
F
OMs
HN
F
O
O
ON
MeO
O
F
O
O
O
1. sesamol Cs2CO3 MeCN, 90 C
2. Pd/C, H2 THF/MeOH
67% (2 steps)d.r. >95:5, 94% ee
KOH
(R,S)-9
EtOHH2Oreflux
CuCl (5 mol %)(R,R)-QuinoxP* (5 mol %)B2(pin)2 (1.2 equiv)
K(O-t-Bu) (20 mol %)MeOD (2 equiv)THF, 10C, 3 h
NO
BnOB(pin)
D/H (D >95%)
NO
BnO2e (R)-4e'
85%, 98% ee
255
Density functional theory (DFT) calculations (B3PW91/cc‐pVDZ) were
performed to prove the origin of an unprecedented regioselectivity of current
borylation of 1,2‐hydropyridines (Figure 2). In this reaction, four different
borylcupration pathways can be considered (path A D, Figure 2). Thus, the
author calculated all borylation pathways using achiral
borylcopper(I)/Me2PCH=CHPMe2 model complex with 2a as a substrate. The
results showed that the activation energies for path A (ΔGTS1) and path C
(ΔGTS3) leading to the stable allylcopper(I) intermediates are relatively lower
than those of path B and D. As for the path C, the steric congestion between a
B(pin) group and a carbamate moiety would cause a destabilization during
the borylcupration process.18 Therefore, the current borylation selectively
proceeds through the 4,3‐borylcupration to form the intermediate P1.
Figure 2. Density Functional Theory Calculation of Four Regioisomeric
Pathways (B3PW91/cc‐pVDZ)
N
CO2Me
NR
CuL NR
CuL
B(pin) B(pin)N
R
CuL
B(pin)
NR
CuL
(pin)B
NR
CuL
(pin)BN
R
LCu(pin)B
∆GC1 = +7.7 ∆GTS1 = +19.0 ∆GP1 =11.5
∆GC3 = +9.4 ∆GTS3 = +20.4 ∆GP3 =8.0
NR
CuL NR CuL
B(pin) B(pin)
NR
B(pin)
CuL
∆GC2 = +8.9 ∆GTS2 = +21.8 ∆GP2 =7.3
NR
LCuB(pin)
NR
LCuB(pin)
NR
(pin)BLCu
∆GC4 = +9.8 ∆GTS4 = +27.0 ∆GP4 =0.9
L = Me2PCH=CHPMe2
4
3
R = -CO2Me
4,3-addition
256
A reaction mechanism for the current copper(I)‐catalyzed
enantioselective borylation of 1,2‐dihydropyridines is proposed based on the
DFT calculations and deuterium labeling experiment as shown in Figure 3.
The reaction of CuCl with the ligand and K(O‐t‐Bu) would result in the
formation of copper(I) alkoxide A, which would initially react with diboron 3
to afford the boryl copper(I) intermediate B. The subsequent addition of B
into 2 would give the allylcopper(I) intermediate C with concomitant
formation of a stereogenic CB bond at 3‐position. The SE2‐type protonation of C by alcohol would produce the corresponding borylation product (path
A). The syn‐stereoselectivity observed in the borylation of
4‐aryl‐1,2‐dihydropyridine was in good agreement with this reaction
mechanism. However, another possible pathway, which would be involved
the isomerization of C leading to D and subsequent SE2’‐type protonation of
D (path B), cannot be completely excluded at this stage.
Figure 3. Proposed Reaction Pathway
Conclusion
In summary, the author has developed the novel
dearomatization/enantioselective protoborylation sequence of pyridines to
afford the chiral 3‐borylpiperidine derivatives with excellent regio‐,
diastereo‐ and enantioselectivity. This methodology provides a simple and
direct way of synthesizing optically active piperidines bearing a
N
CO2R4
LCu B(pin)
CuLB(pin)
R3
R2
R1 N
CO2R4
B(pin)R2
R1
R3
LCu
+ ROHROCuL
isomerization
path ASE2 protonation
path BSE2' protonation
N
CO2R4
R3
R2
R1
borylcupration
N
CO2R4
HB(pin)
R3
R2
R1
+ B2(pin)2ROB(pin)
ROCuLR = Me or tBu
R3 = H, (S)-4R3 = Ar, (R,R)-4
+ K(O-t-Bu), LKCl
CuCl
A
B
2
C D
257
C3‐stereocenter, which are privileged components in a wide variety of
bioactive molecules, in combination with the stereospecific functionalization
of a stereogenic CB bond. Further investigation of stereospecific
transformations including Suzuki‐Miyaura coupling reaction of this novel
3‐borylpiperidines for the synthesis of natural products and pharmaceutical
drugs is now ongoing.
258
Experimental
General.
Materials were obtained from commercial suppliers and purified by
standard procedures unless otherwise noted. Solvents were also purchased
from commercial suppliers, degassed via three freeze‐pump‐thaw cycles, and
further dried over molecular sieves (MS 4Å). NMR spectra were recorded on
JEOL JNM‐ECX400P and JNM‐ECS400 spectrometers (1H: 400 MHz and 13C:
100 MHz).Tetramethylsilane (1H) and CDCl3 (13C) were employed as external
standards, respectively. CuCl (ReagentPlus® grade, 224332‐25G, ≥99%) was
purchased from Sigma‐Aldrich Co. and used as received. 2‐Phenylethyl
chloride was used as an internal standard to determine NMR yields. HPLC
analyses with chiral stationary phase were carried out using a Hitachi
LaChrome Elite HPLC system with a L‐2400 UV detector. High‐resolution
mass spectra was recorded at the Center for Instrumental Analysis,
Hokkaido University.
Procedure for the copper(I)‐catalyzed enantioselective borylation of
1,2‐dihydropyridines 2a (Table 1).
CuCl (2.5 mg, 0.025 mmol) and bis(pinacolato)diboron (151.7 mg, 0.60
mmol), (R,R)‐QuinoxP* (8.4 mg, 0.025 mmol) were placed in an oven‐dried
reaction vial. After the vial was sealed with a screw cap containing a
teflon‐coated rubber septum, the vial was connected to a vacuum/nitrogen
manifold through a needle. It was evacuated and then backfilled with
nitrogen. This cycle was repeated three times. THF (1.0 mL) and
K(O‐t‐Bu)/THF (1.0 M, 0.10 mL, 0.10 mmol) were added in the vial through
the rubber septum. After 2a (69.6 mg, 0.50 mmol) was added to the mixture
at 10 °C, MeOH (40.5 μL, 1.0 mmol) was added dropwise. After the
reaction was complete, the reaction mixture was passed through a short silica
gel column eluting with Et2O. The crude mixture was purified by flash
column chromatography (SiO2, ethyl acetate/hexane, typically 0:100–10:90) to
give the corresponding borylation product (R)‐4a as a colorless oil.
259
Substrate Preparation
The pyridines 1a1h, 1i, 1m and 1o were purchased from
commercial suppliers. The received materials from the suppliers were
subjected to purification by distillation before use. The 4‐arylpyridines
1j11n were synthesized through the standard
Suzuki‐Miyaura coupling reaction of 4‐bromopyridine and the
corresponding arylboronic acids according to the literature procedure.18
Preparation of methyl pyridine‐1(2H)‐carboxylate (2a).19
Methyl chloroformate (2.3 mL, 30.0 mmol) was added dropwise under
nitrogen to a solution of NaBH4 (567.0 mg, 15 mmol), pyridine (1a) (2.4 mL,
30.0 mmol) and MeOH (100.0 mL) at –78 °C. The reaction was maintained at
78 °C for 1 h and then poured into ice ‐water. The product was extracted
with CH2Cl2 three times. The combined organic layer was then dried over
MgSO4. After filtration, the solvents were removed by evaporation. The crude
product was purified by flash column chromatography (SiO2, ethyl
acetate/hexane, 8:92) to obtain 2a (2.97 g, 2.1 mmol, 71%) as a clear liquid,
which was immediately used in the next borylation reaction in order to
prevent decomposition.
The other 1,2‐dihydropyridines 2b2 , 2h 2o were prepared from the
corresponding pyridines according to the procedure described above. As for
the synthesis of 2i, LiBH4 was used instead of NaBH4. The Boc‐protected
1,2‐dihydropyridine 2g was prepared from 2f by the protecting group
exchange reaction with K(O‐t‐Bu).
2a, 71%
NaBH4 (0.5 equiv)ClCO2Me (1.0 equiv)
MeOH, 78 C, 1 h
1a
NNO
MeO
260
Borylation Product Characterization
Methyl
(R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyridine‐1(2
H)‐carboxylate [(R)‐4a].
1H NMR (392 MHz, CDCl3, δ): 1.23 (s, 12H), 1.37–1.48 (m, 1H), 1.98–2.17 (m,
2H), 3.25 (t, J = 11.7 Hz, 0.5H), 3.31 (t, J = 11.5 Hz, 0.5H), 3.91 (d, J = 12.9 Hz,
0.5H), 4.04 (d, J = 12.0 Hz, 0.5H), 4.86–4.93 (m, 0.5H), 4.96–5.03 (m, 0.5H), 6.72
(d, J = 8.1 Hz, 0.5H), 6.86 (d, J = 8.6 Hz, 0.5H). 13C NMR (99 MHz, CDCl3, ):
17.3 (br, BCH), 22.8 and 22.9 (a pair of s, CH2), 24.5 (CH3), 43.1 and 43.3 (a
pair of s, CH2), 52.5 and 52.6 (a pair of s, CH3), 83.1 and 83.2 (a pair of s, C),
106.7 and 107.0 (a pair of s, CH), 124.6 and 125.1 (a pair of s, CH), 153.4 and
153.9 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for C13H22O4N10B, 266.16782;
found, 266.16720. [α]D22.9 51.55 (c 1.0 in CHCl3, 99% ee). The ee value was
determined by HPLC analysis of the corresponding ester after oxidation,
followed by standard acylation with 4‐nitrobenzoyl chloride of the borylated
product in comparison of the racemic sample. Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 7/93, 0.5 mL/min, 40 °C, (R)‐isomer: tR = 33.89 min.,
(S)‐isomer: tR = 36.77 min.
Methyl
(3R,4R)‐4‐phenyl‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydr
opyridine‐1(2H)‐carboxylate [(R,R)‐4b].
1H NMR (392 MHz, CDCl3, δ): 1.09–1.19 (m, 12H), 1.43–1.54 (m, 1H), 3.44–
3.63 (m, 2H), 3.71 (dd, J = 3.2 Hz, 12.6 Hz, 0.5H), 3.77 and 3.78 (a pair of s, 3H),
3.90 (dd, J = 3.4 Hz, 12.8 Hz, 0.5H), 4.90 (dd, J = 2.9 Hz, 8.3 Hz, 0.5H), 5.00 (dd,
J = 3.2 Hz, 8.5 Hz, 0.5H), 6.70 (dd, J = 1.8 Hz and 8.5 Hz, 0.5H), 7.05 (dd, J = 1.4
N
MeO
OB
O
O
(R)-4a
(R,R)-4b
N
MeO
OB
Ph
O
O
261
Hz and 8.1 Hz, 0.5H), 7.15–7.33 (m, 5H). 13C NMR (99 MHz, CDCl3, ): 24.5
and 24.9 (a pair of s, CH3), 27.1 (br, BCH), 39.7 and 40.2 (a pair of s, CH),
41.8 and 42.2 (a pair of s, CH2), 52.8 and 52.9 (a pair of s, CH3), 83.4 and 83.5
(a pair of s, C), 110.4 (CH), 124.9 and 125.6 (a pair of s, CH), 126.27 and 126.31
(a pair of s, CH), 127.8 and 127.9 (a pair of s, CH), 128.1 (CH), 144.9 and 145.1
(a pair of s, C), 153.5 and 154.0 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for
C19H26O4N10B, 342.19912; found, 342.19813. [α]D21.9 63.00 (c 1.5 in CHCl3, 92%
ee). Daicel CHIRALPAK® OZ‐3, 2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C,
(R,R)‐isomer: tR = 9.96 min., (S,S)‐isomer: tR = 11.72 min.
Isopropyl
(R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyridine‐1(2
H)‐carboxylate [(R)‐3c].
1H NMR (392 MHz, CDCl3, δ): 1.18–1.29 (m, 18H), 1.35–1.46 (m, 1H), 1.97–
2.13 (m, 2H), 3.27 (dd, J = 11.2 Hz, 12.6 Hz, 0.6H), 3.37 (dd, J = 10.6 Hz, 12.4
Hz, 0.4H), 3.80 (dd, J = 2.9 Hz, 12.8 Hz, 0.4H), 4.00 (dd, J = 2.7 Hz, 13.0 Hz,
0.6H), 4.87 (quint, J = 3.9 Hz, 0.6H), 4.91–5.04 (m, 1.4H), 6.74 (d, J = 8.5 Hz,
0.6H), 6.85 (d, J = 8.1 Hz, 0.4H). 13C NMR (99 MHz, CDCl3, ): 17.5 (br,
BCH), 22.1 (CH3), 23.0 and 23.1 (a pair of s, CH2), 24.55 and 24.60 (a pair of
s, CH3), 43.0 and 43.2 (a pair of s, CH2), 68.8 (CH), 83.2 and 83.3 (a pair of s, C),
106.2 and 106.6 (a pair of s, CH), 124.9 and 125.3 (a pair of s, CH), 152.7 and
153.2 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for C15H26O4N10B, 294.19912;
found, 294.19826. [α]D21.7 32.83 (c 1.5 in CHCl3, 98% ee). The ee value was
determined by HPLC analysis of the corresponding ester after oxidation,
followed by standard acylation with 4‐nitrobenzoyl chloride of the borylated
product in comparison of the racemic sample.Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 10/90, 0.5 mL/min, 40 °C, (R)‐isomer: tR = 17.52 min.,
(S)‐isomer: tR = 19.44 min.
(R)-4c
N
O
OB
O
O
262
Isobutyl
(R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyridine‐1(2
H)‐carboxylate [(R)‐4d].
1H NMR (392 MHz, CDCl3, δ): 0.95 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.2 Hz,
3H), 1.23 (s, 12H), 1.40–1.50 (m, 1H), 1.89–2.18 (m, 3H), 3.27 (dd, J = 11.0 Hz,
12.4 Hz, 0.5H), 3.47 (dd, J = 9.6 Hz, 12.5 Hz, 0.5H), 3.77–4.08 (m, 3H), 4.89
(quint, J = 4.0 Hz, 0.5H), 4.98 (quint, J = 3.9 Hz, 0.5H), 6.77 (d, J = 8.6 Hz, 0.5H),
6.86 (d, J = 8.2 Hz, 0.5H). 13C NMR (99 MHz, CDCl3, ): 17.3 (br, B CH), 18.9
(CH3), 22.9 and 23.0 (a pair of s, CH2), 24.5 and 24.6 (a pair of s, CH3), 27.8
(CH), 43.1 and 43.3 (a pair of s, CH2), 71.5 and 71.6 (a pair of s, CH2), 83.17
and 83.22 (a pair of s, C), 106.5 and 106.8 (a pair of s, CH), 124.7 and 125.2 (a
pair of s, CH), 153.1 and 153.6 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for
C16H28O4N10B, 308.21477; found, 308.21408. [α]D22.3 38.20 (c 1.0 in CHCl3, 97%
ee). The ee value was determined by HPLC analysis of the corresponding
ester after oxidation, followed by standard acylation with 4‐nitrobenzoyl
chloride of the borylated product in comparison of the racemic sample.
Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 7/93, 0.5 mL/min, 40 °C,
(R)‐isomer: tR = 20.29 min., (S)‐isomer: tR = 22.95 min.
Benzyl
(R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyridine‐1(2
H)‐carboxylate [(R)‐4e].
1H NMR (392 MHz, CDCl3, δ): 1.21 (s, 6H), 1.22 (s, 6H), 1.39–1.50 (m, 1H),
1.98–2.18 (m, 2H), 3.29 (dd, J = 11.0 Hz, 12.9 Hz, 0.5H), 3.45 (dd, J = 10.1 Hz,
12.4 Hz, 0.5H), 3.88 (dd, J = 3.1 Hz, 12.7 Hz, 0.5H), 4.05 (dd, J = 3.1 Hz, 12.7
Hz, 0.5H), 4.89 (quint, J = 3.9 Hz, 0.5H), 5.01 (quint, J = 3.9 Hz, 0.5H), 5.12–
5.26 (m, 2H), 6.80 (d, J = 8.6 Hz, 0.5H), 6.90 (d, J = 8.6 Hz, 0.5H), 7.28–7.43 (m,
(R)-4d
N
O
OB
O
O
(R)-4e
N
BnO
OB
O
O
263
2H). 13C NMR (99 MHz, CDCl3, ): 17.5 (br, B CH), 22.9 and 23.0 (a pair of s,
CH2), 24.5 (CH3), 24.55 (CH3), 24.6 (CH3), 43.3 and 43.4 (a pair of s, CH2), 67.0
and 67.2 (CH2), 83.2 and 83.3 (a pair of s, C), 107.0 and 107.4 (a pair of s, CH),
124.7 and 125.2 (a pair of s, CH), 127.9 (CH), 128.3 (CH), 136.3 and 136.4 (a
pair of s, C), 152.8 and 153.4 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for
C19H26O4N10B, 342.19912; found, 342.19898. [α]D25.7 71.25 (c 1.0 in CHCl3, 97%
ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 1/99, 0.5 mL/min, 40 °C,
(R)‐isomer: tR = 18.39 min., (S)‐isomer: tR = 19.80 min.
Phenyl
(R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyridine‐1(2
H)‐carboxylate [(R)‐4f].
1H NMR (392 MHz, CDCl3, δ): 1.25 (s, 12H), 1.41–1.60 (m, 1H), 2.05–2.24 (m,
2H), 3.40 (dd, J = 10.5 Hz, 12.9 Hz, 0.5H), 3.60 (dd, J = 10.5 Hz, 12.9 Hz, 0.5H),
5.00–5.07 (m, 0.5H), 5.08–5.16 (m, 0.5H), 6.89 (d, J = 8.6 Hz, 0.5H), 6.96 (d, J =
8.6 Hz, 0.5H), 7.09–7.17 (m, 2H), 7.17–7.25 (m, 1H), 7.32–7.41 (m, 2H). 13C
NMR (99 MHz, CDCl3, ): 17.4 (br, B CH), 24.56 (CH3), 24.61 (CH3), 24.7
(CH3), 43.6 and 44.1 (a pair of s, CH2), 83.3 and 83.4 (a pair of s, C), 108.0 and
108.5 (a pair of s, CH), 121.5 and 121.6 (a pair of s, CH), 124.7 and 125.0 (a
pair of s, CH), 125.2 and 125.3 (a pair of s, CH), 129.1 (CH), 151.0 and 151.1 (a
pair of s, C), 151.3 and 152.0 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for
C18H24O4N10B, 328.18347; found, 328.18273. [α]D25.7 71.25 (c 1.0 in CHCl3, 93%
ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 7/93, 0.5 mL/min, 40 °C,
(S)‐isomer: tR = 13.64 min., (R)‐isomer: tR = 15.39 min.
(R)-4f
N
PhO
OB
O
O
264
tert‐Butyl
(R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyridine‐1(2
H)‐carboxylate [(R)‐4g].
1H NMR (392 MHz, CDCl3, δ): 1.22 (s, 12H), 1.48 (s, 9H), 1.65–1.72 (m, 1H),
1.97–2.15 (m, 2H), 3.22 (t, J = 11.7 Hz, 0.6H), 3.36 (t, J = 11.2 Hz, 0.4H), 3.77 (d,
J = 11.3 Hz, 0.4H), 4.00 (d, J = 11.3 Hz, 0.6H), 4.79–4.88 (m, 0.6H), 4.90–4.98 (m,
0.4H), 6.71 (d, J = 8.1 Hz, 0.6H), 6.84 (d, J = 8.1 Hz, 0.4H). 13C NMR (99 MHz,
CDCl3, ): 17.6 (br, B CH), 23.1 (CH2), 24.6 (CH3), 28.3 (CH2), 42.7 and 43.6
(a pair of s, CH2), 80.2 (C), 83.3 (C), 105.8 and 106.3 (a pair of s, CH), 125.2 and
125.5 (a pair of s, CH), 152.2 and 152.7 (a pair of s, C). HRMS–EI (m/z): [M]+
calcd for C16H28O4N10B, 308.21477; found, 308.21406. [α]D25.1 52.91 (c 1.0 in CHCl3, 97% ee). The ee value was determined by HPLC analysis of the
corresponding ester after oxidation, followed by standard acylation with
4‐nitrobenzoyl chloride of the borylated product in comparison of the
racemic sample.Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 7/93, 0.5
mL/min, 40 °C, (R)‐isomer: tR = 17.33 min., (S)‐isomer: tR = 20.40 min.
Methyl
(R)‐6‐methyl‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyri
dine‐1(2H)‐carboxylate [(R)‐4h].
1H NMR (392 MHz, CDCl3, δ): 1.23 (s, 12H), 1.37–1.48 (m, 1H), 2.02–2.20 (m,
2H), 2.06 (s, 3H), 3.28 (dd, J = 9.9 Hz and 13.0 Hz, 1H), 3.91 (s, 3H), 3.98 (dd, J
= 3.2 Hz and 12.5 Hz, 1H), 4.89–4.94 (m, 1H). 13C NMR (99 MHz, CDCl3, ):
18.8 (br, BCH), 22.1 (CH3), 24.5 (CH2), 24.6 (CH3), 45.8 (CH2), 52.3 (CH3), 83.2
(C), 111.6 (CH), 135.1 (C), 154.7 (C). HRMS–EI (m/z): [M]+ calcd for
C14H24O4N10B, 280.18347; found, 280.18248. [α]D23.3 64.18 (c 1.1 in CHCl3, 92%
N
O
OB
(R)-4g
O
O
(R)-4h
N
MeO
OB
Me
O
O
265
ee). The ee value was determined by HPLC analysis of the corresponding
ester after oxidation, followed by standard acylation with 4‐nitrobenzoyl
chloride of the borylated product in comparison of the racemic sample.
Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 7/93, 0.5 mL/min, 40 °C,
(R)‐isomer: tR = 22.67 min., (S)‐isomer: tR = 33.55 min.
Methyl
(R)‐6‐propyl‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,4‐dihydropyri
dine‐1(2H)‐carboxylate [(R)‐4i].
1H NMR (392 MHz, CDCl3, δ): 0.84 (t, J = 7.4 Hz, 3H), 1.23 (s, 12H), 1.30–
1.48 (m, 3H), 2.04–2.31 (m, 3H), 2.64 (quint, J = 6.9 Hz, 1H), 3.19 (dd, J = 10.3
Hz, 12.6 Hz), 3.71 (s, 3H), 4.02 (dd, J = 3.1 Hz, 12.6 Hz), 5.01 (t, J = 3.6 Hz, 1H). 13C NMR (99 MHz, CDCl3, ): 13.5 ( CH3), 19.2 (br, BCH), 20.8 (CH2), 24.5
(CH2), 24.67 (CH3), 24.70 (CH3), 36.9 (CH2), 46.1 (CH2), 52.4 (CH3), 83.3 (C),
112.6 (CH), 139.3 (CH), 154.7 (C). HRMS–EI (m/z): [M]+ calcd for C16H28O4N10B,
308.21477; found, 308.21368. [α]D23.5 55.22 (c 0.9 in CHCl3, 96% ee). The ee
value was determined by HPLC analysis of the corresponding ester after
oxidation, followed by standard acylation with 4‐nitrobenzoyl chloride of the
borylated product in comparison of the racemic sample. Daicel
CHIRALPAK® OZ‐3, 2‐PrOH/Hexane = 10/90, 0.5 mL/min, 40 °C, (S)‐isomer:
tR = 21.15 min., (R)‐isomer: tR = 25.25 min.
Methyl
(3R,4R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐4‐(p‐tolyl)‐3,4‐dihydr
opyridine‐1(2H)‐carboxylate [(R,R)‐4j].
1H NMR (392 MHz, CDCl3, δ): 1.08–1.22 (m, 12H), 1.41–1.52 (m, 1H), 2.31 (s,
(R)-4i
N
MeO
OB
Me
O
O
N
MeO
OB
Me
(R,R)-4j
O
O
266
3H), 3.44–3.62 (m, 2H), 3.67 (dd, J = 3.4 Hz, 12.9 Hz, 0.5H), 3.77 and 3.78 (a
pair of s, 3H), 3.86 (dd, J = 3.4 Hz, 12.4 Hz, 0.5H), 4.88 (dd, J = 2.9 Hz, 8.2 Hz,
0.5H), 5.00 (dd, J = 3.4 Hz, 8.1 Hz, 0.5H), 6.88 (dd, J = 1.4 Hz, 8.1 Hz, 0.5H),
7.03 (dd, J = 1.4 Hz, 8.1 Hz, 0.5H), 7.05–7.18 (m, 5H). 13C NMR (99 MHz,
CDCl3, ): 21.1 ( CH3), 24.7 (CH3), 24.8 (CH3), 27.3 (br, BCH), 39.4 and 39.9
(a pair of s, CH), 41.9 and 42.3 (a pair of s, CH2), 52.9 and 53.0 (a pair of s,
CH3), 83.58 and 83.63 (a pair of s, C), 110.8 (CH), 125.0 and 125.7 (a pair of s,
CH), 127.9 and 128.0 (a pair of s, CH), 129.0 (CH), 135.9 (C), 142.1 and 142.3 (a
pair of s, C), 153.7 and 154.2 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for
C20H28O4N10B, 356.21477; found, 356.21385. [α]D25.7 56.00 (c 1.0 in CHCl3, 95%
ee). Daicel CHIRALPAK® OZ‐3, 2‐PrOH/Hexane = 3/97, 0.5 mL/min, 40 °C,
(R,R)‐isomer: tR = 11.63 min., (S,S)‐isomer: tR = 12.69 min.
Methyl
(3R,4R)‐4‐(4‐methoxyphenyl)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)
‐3,4‐dihydropyridine‐1(2H)‐carboxylate [(R,R)‐4k].
1H NMR (392 MHz, CDCl3, δ): 1.08–1.22 (m, 12H), 1.40–1.49 (m, 1H), 3.42–
3.61 (m, 2H), 3.70 (dd, J = 3.4 Hz, 12.9 Hz, 0.5H), 3.78 (s, 6H), 3.89 (dd, J = 3.4
Hz, 12.9 Hz, 0.5H), 4.87 (dd, J = 2.9 Hz, 8.6 Hz, 0.5H), 4.98 (dd, J = 3.4 Hz, 8.6
Hz, 0.5H), 6.81 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 0.5H), 7.02 (d, J = 8.6 Hz,
0.5H), 7.15 (d, J = 8.1 Hz, 2H). 13C NMR (99 MHz, CDCl3, ): 24.5 ( CH3), 24.6
(CH3), 27.1 (br, BCH), 38.9 and 39.3 (a pair of s, CH), 41.9 and 42.2 (a pair of
s, CH2), 52.7 and 52.8 (a pair of s, CH3), 55.1 (CH3), 83.37 and 83.43 (a pair of s,
C), 110.8 (CH), 113.5 (CH), 124.7 and 125.4 (a pair of s, CH), 128.7 and 128.8 (a
pair of s, CH), 137.0 and 137.2 (a pair of s, C), 153.5 and 154.0 (a pair of s, C),
158.0 (C). HRMS–EI (m/z): [M]+ calcd for C20H28O5N10B, 372.20968; found,
372.20878. [α]D22.7 64.18 (c 0.8 in CHCl3, 96% ee). Daicel CHIRALPAK® OZ‐3,
2‐PrOH/Hexane = 3/97, 0.5 mL/min, 40 °C, (R,R)‐isomer: tR = 41.76 min.,
(S,S)‐isomer: tR = 45.68 min.
N
MeO
OB
OMe
(R,R)-4k
O
O
267
Methyl
(3R,4R)‐4‐(4‐fluorophenyl)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3,
4‐dihydropyridine‐1(2H)‐carboxylate [(R,R)‐4l].
1H NMR (392 MHz, CDCl3, δ): 1.09–1.20 (m, 12H), 1.39–1.49 (m, 1H), 3.40–
3.61 (m, 2H), 3.73 (dd, J = 3.2 Hz, 12.6 Hz, 0.5H), 3.78 and 3.79 (a pair of s, 3H),
3.92 (dd, J = 3.1 Hz, 13.0 Hz, 0.5H), 4.84 (dd, J = 2.9 Hz, 8.3 Hz, 0.5H), 4.96 (dd,
J = 3.2 Hz, 8.5 Hz, 0.5H), 6.89 (dd, J = 1.6, 8.3 Hz, 0.5H), 6.94 (d, J = 8.5 Hz, 1H),
6.97 (d, J = 8.5 Hz, 1H), 7.04 (dd, J = 1.4 Hz, 8.5 Hz, 0.5H), 7.15–7.23 (m, 2H). 13C NMR (99 MHz, CDCl3, ): 24.5 ( CH3), 24.7 (CH3), 27.8 (br, BCH), 39.1
and 39.6 (a pair of s, CH), 42.0 and 42.3 (a pair of s, CH2), 52.9 and 53.0 (a pair
of s, CH3), 83.5 and 83.6 (a pair of s, C), 110.3 (CH), 114.8 and 115.0 (a pair of
CH), 125.1 and 125.7 (a pair of s, CH), 129.3 (C F, d, J = 7.6 Hz, CH), 129.4
(C F, d, J = 7.6 Hz, CH), 140.6 and 140.8 (a pair of s, C), 153.8 (C F, d, J =
213.1 Hz, CH), 160.2 and 162.7 (a pair of s, C). HRMS–EI (m/z): [M]+ calcd for
C19H25O5N10BF, 360.18970; found, 360.18876. [α]D18.6 +38.09 (c 2.3 in CHCl3,
96% ee). Daicel CHIRALPAK® OJ‐3, 2‐PrOH/Hexane = 0.5/99.5, 0.5 mL/min,
40 °C, (R,R)‐isomer: tR = 15.41 min., (S,S)‐isomer: tR = 17.20 min.
Methyl
(3R,4R)‐4‐(3‐bromophenyl)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐3
,4‐dihydropyridine‐1(2H)‐carboxylate [(R,R)‐4m].
1H NMR (392 MHz, CDCl3, δ): 1.09–1.23 (m, 12H), 1.38–1.48 (m, 1H), 3.39–
3.65 (m, 2H), 3.71 (dd, J = 3.1 Hz, 12.7 Hz, 0.5H), 3.79 (s, 3H), 3.91 (dd, J = 2.9
Hz, 12.9 Hz, 0.5H), 4.85 (dd, J = 2.4 Hz, 8.6 Hz, 0.5H), 4.96 (dd, J = 2.9 Hz, 8.6
N
MeO
OB
F
(S,S)-4l
O
O
(R,R)-4m
N
MeO
OB
Br
O
O
268
Hz, 0.5H), 6.92 (d, J = 8.6 Hz, 0.5H), 7.07 (d, J = 8.1 Hz, 0.5H), 7.10–7.22 (m,
2H), 7.32 (dt, J = 2.0 Hz, 7.0 Hz, 1H), 7.39 (br, s, 1H). 13C NMR (99 MHz,
CDCl3, ): 24.5 ( CH3), 24.7 (CH3), 27.3 (br, BCH), 39.4 and 39.9 (a pair of s,
CH), 41.8 and 42.1 (a pair of s, CH), 52.8 and 52.9 (a pair of s, CH3), 83.6 (C),
109.3 and 109.4 (a pair of s, CH), 122.1 (C), 125.5 and 126.1 (a pair of s, CH),
126.3 and 126.4 (a pair of s, CH), 129.3 (CH), 129.7 (CH), 131.1 and 131.2 (a
pair of s, CH), 147.4 and 147.6 (a pair of s, C), 153.4 and 153.9 (a pair of s, C).
HRMS–EI (m/z): [M]+ calcd for C19H25O4N10BBr, 420.10963; found, 420.10843.
[α]D24.2 72.50 (c 1.0 in CHCl3, 74% ee). The ee value was determined by HPLC
analysis of the corresponding ester after oxidation, followed by standard
esterification with p‐nitrobenzoyl chloride of the borylated product in
comparison of the racemic sample. Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 7/93, 0.5 mL/min, 40 °C, (R,R)‐isomer: tR = 36.08 min.,
(S,S)‐isomer: tR = 38.99 min.
Methyl
(3R,4R)‐3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐4‐(3‐(trifluoromethyl
)phenyl)‐3,4‐dihydropyridine‐1(2H)‐carboxylate [(R,R)‐4n].
1H NMR (392 MHz, CDCl3, δ): 1.03–1.23 (m, 12H), 1.46 (t, J = 8.4 Hz, 1H),
3.39–3.55 (m, 1H), 3.61–3.69 (m, 1H), 3.73–3.84 (m, 3.5H), 3.96 (dd, J = 3.5, 12.9
Hz, 0.5H), 4.86 (dd, J = 2.4, 8.6 Hz, 0.5H), 4.96 (dd, J = 2.6, 8.3 Hz, 0.5H), 6.95
(d, J = 8.1 Hz, 0.5H), 7.09 (d, J = 8.2 Hz, 0.5H), 7.35–7.55 (m, 4H). 13C NMR (99
MHz, CDCl3, ): 24.5 ( CH3), 24.6 (CH3), 27.3 (br, BCH), 39.7 and 40.1 (a
pair of s, CH), 42.0 and 42.3 (a pair of s, CH2), 52.9 and 53.0 (a pair of s, CH3),
83.7 (C), 109.4 and 109.5 (a pair of s, CH), 123.3 (CH), 125.0 (CH), 125.7 (CH),
126.3 (CH), 128.7 (CH), 130.3 (CF, q, J = 33.4 Hz, C), 131.2 (CH), 146.1 and
146.2 (a pair of s, C), 153.5 and 154.0 (a pair of s, C). HRMS–EI (m/z): [M]+
calcd for C20H25O4N10BF3, 410.18650; found, 410.18546. [α]D24.4 47.97 (c 1.5 in CHCl3, 66% ee). The ee value was determined by HPLC analysis of the
corresponding ester after oxidation, followed by standard esterification with
(R,R)-4n
N
MeO
OB
CF3
O
O
269
p‐nitrobenzoyl chloride of the borylated product in comparison of the
racemic sample. Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 10/90, 0.5
mL/min, 40 °C, (R,R)‐isomer: tR = 21.47 min., (S,S)‐isomer: tR = 24.24 min.
Borylation Product Functionalization Procedure
Procedure for the synthesis of chiral piperidinol (R)‐5 through the
oxidation following acylation and hydrogenation of (R)‐4a.
The oxidation was performed according to the literature procedure.20 In a
reaction vial, (R)‐4a (80.2 mg, 0.30 mmol) was dissolved in THF/H2O (1:1, 2.0
mL). NaBO3•4H2O (184.6 mg, 1.2 mmol) was then added at room
temperature. After stirred for 1 h, the reaction mixture was extracted three
times with CH2Cl2, dried over MgSO4, and filtered. The resulting crude
material was used in the next reaction without further purification.
The crude material, 4‐dimethylaminopyridine (7.3 mg, 0.060 mmol) and
pyridine (48.3 μL, 0.60 mmol) were dissolved in dry CH2Cl2 (1.0 mL) under a
nitrogen atmosphere. Benzoic anhydride (67.9 mg, 0.30 mmol) was then
added at room temperature. Aqueous NH4Cl was added to the reaction
mixture after 2 h, the mixture was then extracted with CH2Cl2 three times
and dried over MgSO4, filtered and concentrated under reduced pressure.
The crude mixture was purified by flash column chromatography (SiO2, ethyl
acetate/hexane, 1:99–15:85) to afford the corresponding ester (63.5 mg, 0.24
mmol, 81%) as a colorless oil.
The obtained ester (63.5 mg, 0.24 mmol) and Pd/C (10.0 mg, 10%) were
dissolved in MeOH/THF (1:1, 2.0 mL) under a nitrogen atmosphere.
Hydrogen gas was then introduced to the reaction mixture. After being
stirred for 1 hour, the mixture was filtered through short pad of silica gel
with Et2O as an eluent. The solvent was removed by evaporation under
reduced pressure to obtain the chiral piperidinol (R)‐5 (60.8 mg, 0.23 mmol,
95%) as a colorless oil.
1. NaBO34H2O2. (PhCO)2O, pyridine DMAP, CH2Cl2
3. Pd/C, H2 THF/MeOH(R)-4a
99% ee
N
MeO
OO
O
(R)-577% (3 steps)
98% ee
N
MeO
OB(pin)
270
1H NMR (392 MHz, CDCl3, δ): 1.54–1.72 (m, 1H), 1.76–2.08 (m, 3H), 3.24–
3.92 (m, 4H), 3.54 (s, 3H), 5.03–5.16 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.57 (t, J =
7.4 Hz, 1H), 7.99–8.05 (m, 2H). 13C NMR (99 MHz, CDCl3, ): 21.4 ( CH2), 29.0
(CH2), 44.2 (CH2), 47.5 (CH2), 52.5 (CH3), 68.2 (CH), 128.3 (CH), 129.5 (CH),
130.1 (C), 133.0 (CH), 156.2 (C), 165.6 (C). HRMS–EI (m/z): [M OMe] + calcd
for C13H14O3N, 232.09737; found, 232.09707. [α]D20.9 15.88 (c 1.2 in CHCl3, 98%
ee). Daicel CHIRALPAK® OD‐3, 2‐PrOH/Hexane = 10/90, 0.5 mL/min, 40 °C,
(R)‐isomer: tR = 14.75 min., (S)‐isomer: tR = 15.60 min.
Procedure for the synthesis of (S)‐7 through the hydrogenation following
cross‐coupling with (3‐methoxyphenyl)lithium of (R)‐4a.
The borylation product (R)‐4a (155.6 mg, 0.58 mmol) and Pd/C (20.0 mg,
10%) were dissolved in MeOH/THF (1:1, 1.0 mL) under a nitrogen
atmosphere. Hydrogen gas was then introduced to the reaction mixture.
After being stirred for 15 hour, the mixture was filtered through short pad of
silica gel with Et2O as an eluent. The solvent was removed by evaporation
under reduced pressure to obtain the chiral piperidine (150.5 mg, 0.56 mmol,
96%) as a colorless oil.
The stereospecific cross‐coupling was performed according to the
literature procedure.14 A solution of 1‐bromo‐3‐methoxybenzene (29.0 μL,
0.23 mmol) in THF (1.0 mL) was cooled to –78 °C and treated with n‐BuLi in
hexane (1.63 M, 141.0 μL 0.24 mmol). After being stirred for 1 h at –78 °C, a
THF solution (1.0 ml) of (R)‐4a (51.1 mg, 0.19 mmol) was added to the
reaction mixture. After being stirred for 1 h at –78 °C, the solvent was
removed under reduced pressure and MeOH (2.0 ml) was added to the
mixture. A THF solution (3.0 mL) of N‐bromoscuccinimide (NBS) was then
(R)-4a99% ee
N
MeO
OB(pin)
Pd/C, H2
THF/MeOH
Li OMe
1. (1.2 equiv)
2. NBS, MeOH, 78 C
N
MeO
O OMe
(S)-751%, 98% ee
N
MeO
OB(pin)
271
added at –78 °C and the reaction stirred at the same temperature for 1 h.
Aqueous Na2S2O3 was added and the reaction mixture was allowed to warm
to room temperature. The mixture was extracted three times with CH2Cl2,
dried over MgSO4, and filtered. The crude material was purified by flash
column chromatography (SiO2, EtOAc/hexane, 2:98–15:85) to give the
arylated product (S)‐7 (24.2 mg, 0.097 mmol, 51%) as a colorless oil. 1H NMR (392 MHz, CDCl3, δ): 1.51–1.70 (m, 2H), 1.71–1.82 (m, 1H), 1.98–
2.07 (m, 1H), 2.59–2.86 (m, 3H), 3.70 (s, 3H), 3.81 (s, 3H), 4.03–4.45 (m, 2H),
6.74–6.80 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H), 7.19–7.25 (m, 1H). 13C NMR (99
MHz, CDCl3, ): 25.4 ( CH2), 31.6 (CH2), 42.7 (CH), 44.2 (CH2), 50.5 (CH2), 52.5
(CH3), 55.1 (CH3), 111.6 (CH), 113.1 (CH), 119.4 (CH), 129.5 (CH), 144.9 (C),
155.9 (C), 159.7 (C). HRMS–EI (m/z): [M]+ calcd for C14H19O3N, 249.13649;
found, 249.13599. [α]D21.2 12.67 (c 1.5 in CHCl3, 98% ee). Daicel
CHIRALPAK® IC‐3, 2‐PrOH/Hexane = 5/95, 0.5 mL/min, 40 °C, (S)‐isomer: tR
= 28.71 min., (R)‐isomer: tR = 29.81 min.
Procedure for the synthesis of (R,S)‐7 through derivatization of (S,S)‐4l.
The one‐carbon homologation was performed according to the literature
procedure.16 In an oven‐dried reaction vial, (S,S)‐4l (436.3 mg, 1.2 mmol) and
bromochloromethane (160.9 μL, 2.4 mmol) were dissolved in dry THF (9.0
mL) in nitrogen atmosphere. After the mixture was cooled to –78 °C, n‐BuLi
in hexane (1.64 M, 1.1 mL, 1.8 mmol) was added dropwise. The mixture was
stirred at –78 °C for 20 min, and then stirred at room temperature for 2 h. The
reaction mixture was quenched by the addition of aqueous NH4Cl, extracted
( )-paroxetineantidepressant drug
(R,S)-1061%
d.r. 97:396% ee
(S,S)-4l
3. MsCl, Et3N
1. LiCH2Cl,78 C2. NaBO34H2O
(R,S)-884% (3 steps), d.r. 97:3
N
MeO
O
F
OMs
HN
F
O
O
ON
MeO
O
F
O
O
O
1. sesamol Cs2CO3 MeCN, 90 C
2. Pd/C, H2 THF/MeOH
67% (2 steps)d.r. >95:5, 94% ee
KOH
(R,S)-9
EtOHH2Oreflux
272
three times with CH2Cl2, dried over MgSO4, and filtered. The crude material
was purified by flash column chromatography (SiO2, EtOAc/hexane, 2.5:97.5–
12.5:87.5) to give the homologation product (432.1 mg, 1.2 mmol, 96%) as a
colorless oil.
The oxidation was performed according to the procedure described above.
In a reaction vial, the homologation product (432.1 mg, 1.2 mmol) was
dissolved in THF/H2O (1:1, 6.0 mL). NaBO3•4H2O (709.0 mg, 4.6 mmol) was
then added at room temperature. After stirred for 30 min, the reaction
mixture was extracted three times with CH2Cl2, dried over MgSO4, and
filtered. The resulting crude material was used in the next reaction without
further purification.
The crude material and Et3N (481.7 μL, 3.5 mmol) were dissolved in dry
CH2Cl2 (2.0 mL) under a nitrogen atmosphere. Methanesulfonyl chloride
(178.3 μl, 2.3 mmol) was then added at 0 °C. After being stirred for 3 h at
room temperature, aqueous NaHCO3 was added to the reaction mixture. The
mixture was then extracted with CH2Cl2 three times and dried over MgSO4,
filtered and concentrated under reduced pressure. The crude mixture was
purified by flash column chromatography (SiO2, ethyl acetate/hexane,
7.5:92.5–50:50) to afford the corresponding mesylate (350.0 mg, 1.0 mmol,
88%, 2 steps) as a colorless oil.
In a vacuum dried 100 mL round bottomed flask, the mesylate (350.0 mg,
1.0 mmol), sesamol (281.6 mg, 2.0 mmol) and Cs2CO3 (1.3 g, 4.1 mmol) were
dissolved in dry MeCN (15.0 mL) and it was warmed to 90 °C under nitrogen
atmosphere. After being stirred for 12 h, the reaction mixture was quenched
by addition of aqueous NH4Cl and extracted with CH2Cl2 three times. The
combined organic layer was then dried over MgSO4. After filtration, the
solvents were removed by evaporation. The crude product was then purified
by flash column chromatography (SiO2, ethyl acetate/hexane, 3:97–15:85) to
afford the corresponding ether (276.7 mg, 0.72 mmol, 70%) after the
treatment with tert‐butyldimethylchlorosilane (TBSCl) and imidazole to
remove the cesamol as the silylether by silica gel column.
The ester (276.7 mg, 0.72 mmol) and Pd/C (20.0 mg, 10%) were dissolved
in MeOH/THF (1:1, 2.0 mL) under a nitrogen atmosphere. Hydrogen gas was
then introduced to the reaction mixture. After being stirred for 1 hour, the
mixture was filtered through short pad of silica gel with Et2O as an eluent.
The solvent was removed by evaporation under reduced pressure to obtain
273
the N‐protected ()‐Paroxeine (R,S)‐9 (265.5 mg, 0.68 mmol, 95%) as a
colorless oil. 1H NMR (392 MHz, CDCl3, δ): 1.73 (dt, J = 3.4 and 12.5 Hz, 1H), 1.79–1.88
(m, 1H), 1.96–2.07 (m, 1H), 2.64–2.77 (m, 1H), 2.87 (t, J = 12.3 Hz, 2H), 3.45 (dd,
J = 6.3, 9.4 Hz, 1H), 3.60 (dd, J = 2.7, 9.4 Hz, 1H), 3.74 (s, 3H), 4.19–4.60 (m,
2H), 5.89 (s, 2H), 6.14 (dd, J = 2.7 Hz and 8.5 Hz, 1H), 7.35–7.55 (m, 4H). 13C
NMR (99 MHz, CDCl3, ): 33.7 ( CH2), 41.8 (CH), 43.8 (CH), 44.3 (CH2), 47.2
(CH2), 52.6 (CH3), 68.6 (CH2), 97.9 (CH2), 101.0 (CH2), 105.4 (CH), 107.7 (CH),
115.3 and 115.5 (a pair of s, CH), 128.6 and 128.7 (a pair of s, CH), 138.8 and
138.9 (a pair of s, C), 141.6 (C), 148.1 (C), 154.1 (C), 155.8 (C), 160.2 and 162.7
(a pair of s, C). HRMS–EI (m/z): [M]+ calcd for C21H22O5NF, 387.14820; found,
387.14779. [α]D22.8 +14.35 (c 1.0 in CHCl3, 93% ee). Daicel CHIRALPAK® OD‐3,
2‐PrOH/Hexane = 10/90, 0.5 mL/min, 40 °C, (S,R)‐isomer: tR = 23.49 min.,
(R,S)‐isomer: tR = 27.17 min.
The N‐protected ()‐Paroxeine (R,S)‐9 (96.9 mg, 0.25 mmol) was dissolved
in EtOH/H2O (4:1, 1.9 ml). Potassium hydroxide (420.8 mg, 7.5 mmol) was
then added to a reaction mixture. After being stirred for 42 hours at 110℃,
the mixture was then extracted with CH2Cl2 three times and dried over
MgSO4, filtered and concentrated under reduced pressure to afford
()‐Paroxeine (265.5 mg, 0.68 mmol, 61%) as a yellow oil. 1H and 13C NMR
were in agreement with those in the literature.
1H NMR (392 MHz, CDCl3, δ): 1.64–1.85 (m, 3H), 2.00–2.11 (m, 1H), 2.58
(dt, J = 4.0 and 11.7 Hz, 1H), 2.62–2.79 (m, 2H), 3.18 (d, J = 12.2 Hz, 1H), 3.37–
3.46 (m, 2H), 3.55 (dd, J = 3.1, 9.4 Hz, 1H), 5.86 (s, 2H), 6.11 (dd, J = 2.7 Hz and
8.5 Hz, 1H), 6.32 (d, J = 2.7 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 6.92–7.01 (m, 2H),
7.11–7.19 (m, 2H). 13C NMR (99 MHz, CDCl3, ): 32.8 ( CH2), 41.2 (CH), 43.1
(CH), 45.7 (CH2), 48.6 (CH2), 68.4 (CH2), 97.8 (CH), 101.0 (CH2), 105.4 (CH),
107.8 (CH), 115.5 (CF, d, J = 86.0 Hz, CH), 128.8 (CF, d, J = 128.8 Hz, CH),
138.6 (C), 141.7 (C), 148.1 (C), 154.0 (C), 161.6 (CF, d, J = 246.4 Hz, C).
HRMS–EI (m/z): [M]+ calcd for C19H20O3NF, 329.14272; found, 329.14205.
[α]D20.5 92.79 (c 1.2 in CHCl3).
Determination of the Absolute Configurations of Borylation Products
The absolute configuration of borylation product (R)‐4e was determined
by comparison of the optical rotation of the alcohol (R)‐11 [[α]D20 16.24 ( c
274
1.1 in CHCl3)] and the literature value for (R)‐11.21
The anti configuration of borylation product (R,R)‐4b was confirmed by
NOE analysis as shown below.
Details of the DFT Calculations
All calculations were performed with the Gaussian 09W (revision C.01)
program package.22 Geometry optimizations were performed with
B3PW91/cc‐pVDZ in the gas‐phase. The frequency calculations were
conducted on gas‐phase optimized geometries to check the all the stationary
points as either minima or transition states.
Figure S1. Optimized Structures (I, II, C, TS, P) for Four Regioisomeric
Pathway with Structual Parameters and Free Energies.
2. Et3SiH (10 equiv) TFA (12.5 equiv) CH2Cl2, 30C, 15 h
1. NaBO34H2O THF/H2O, 30 min
N
BnO
OB(pin)
97% ee
N
BnO
OOH
55% (2 steps)
(R)-4e (R)-11[]D =16.24
N CO2Me
H
H
B
H
2.2%
major isomer (anti)
N CO2Me
H
H
B
3.5%
minor isomer (syn)
B = B(pin)
275
276
277
Figure S2. DFT Calculations (B3PW91/cc‐pVDZ) of the Transition States
for the (R,R)‐QuinoxP*/Copper(I) Catalyzed Enantioselective Borylation of
1,2‐Dihydropyridine. Relative G values (Kcal/mol) at 298 K, 1.0 atom in
the Gas Phase.
The DFT study suggested that favored Si‐face borylcupration of
1,2‐dihydropyridine would provide (R)‐enantiomer product, which
corresponds to the experimental results.
P Cu P
BO O N
CO2Me
II
IV
I
III
PCu P
BO O
II
IV
I
III
NMeO2C
278
Optimization of the Reaction Conditions for the Borylation of 2b
(R,R)-QuinoxP*
(R)-SEGPHOS
(R)-DM-SEGPHOS
(R,R)-BDPP
(R,R)-Me-Duphos
(R)-SEGPHOSb
(R)-SEGPHOS
chiral ligand conv. (%)a d.r.a ee (%)
>95
>95
>95
>95
>95
75 (61)c
>95 (94)c
99:1
69:31
94:6
96:4
99:1
94:6
97:3
39
91
83
71
36
91
92
aDetermined by GC analysis. b10 mol % catalyst was used and the reaction time was 18 h. cDetermined by 1H NMR analysis. NMR yield is shown in parenthesis.
CuCl (5 mol %)ligand (5 mol %)B2(pin)2 (1.2 equiv)
K(O-t-Bu) (20 mol %) t-BuOH (2.0 equiv)0 C, 2 h2b (R,R)-4b
NO
MeO
NO
MeO
B(pin)
Ph Ph
solvent
THF
THF
THF
THF
THF
toluene/THF (10:1)
toluene/DME/THF (6:6:1)
279
References and Notes
(1) Pyridine and its Derivatives in Heterocycles in Natural Product Synthesis,
Majumdar, K. C.; Chattopadhyay, S. K., Ed.; Wiley‐VCH, Weinheim, 2011,
Chap. 8, pp. 267.
(2) General reviews on piperidines, see: (a) Michael, J. P. Nat. Prod. Rep. 2008,
25, 139. (b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (c) Laschat, S.; Dickner,
T. Synthesis 2000, 1781.
(3) Recent reviews on catalytic enantioselective dearomatization reactions,
see: (a) Zhuo, C.; Zhang, W.; You, S. –L. Angew. Chem., Int. Ed. 2012, 51, 12662.
(b) Ding, Q.; Zhou, X.; Fan, R.; Org. Biomol. Chem. 2014, 12, 4807. (c) Zhuo, C.
–X.; Zheng, C.; You, S. –L. Acc. Chem. Res. 2014, 47, 2558.
(4) Reviews on the synthesis and applications of 1,2‐dihydropyr‐ idines, see:
(a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112,
2642. (b) Silva, E. M. P.; Varandas, P. A. M. M.; Silva, A. M. S. Synthesis 2013,
3053. (c) Tanaka, K.; Fukase, K.; Katsumura, S. Synlett 2011, 2115.
(5) Kubota, K.; Hayama, K.; Iwamoto, H.; Ito. H. Angew. Chem., Int. Ed. 2015,
54, 8809.
(6) For selected examples of copper(I)‐catalyzed enantioselective borylation
reactions from Ito and Sawamura group, see: (a) Ito, H.; Ito, S.; Sasaki, Y.;
Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856 (b) Ito, H.;
Kunii, S.; Sawamura, M. Nat. Chem. 2010, 2, 972 (c) Kubota, K.; Yamamoto,
E.; Ito, H.; Adv. Synth. Catal. 2013, 355, 3527 (d) Yamamoto, E.; Takenouchi,
Y.; Ozaki, T.; Miya, T.; Ito, H. J. Am. Chem. Soc. 2014, 136, 16515. (e) Kubota,
K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 420.
(7) For selected examples of the copper(I)‐catalyzed enantioselective
protoboration reaction, see: (a) Lillo, V.; Prieto, A.; Bonet, A.; Diaz‐Requejo,
M. M.; Ramirez, J.; Pérez, P. J.; Fernández E. Organometallics 2009, 28, 659. (b)
Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160. (c) Noh, D.; Chea,
H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48, 6062. (d) Lee, J. C. H.;
McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894. (e) He, Z. T.; Zhao, Y. S.;
Tian, P.; Wang, C. C.; Dong, H. Q.; Lin, G. Q. Org. Lett. 2014, 16, 1426. (f)
Parra, A.; Amenós, L.; Guisán‐Ceinos, M.; López, A.; Ruano, J. L. G.; Tortosa,
M. J. Am. Chem. Soc. 2014, 136, 15833. (g) Lee, H.; Lee, B. Y.; Yun, J. Org. Lett.
2015, 17, 764.
280
(8) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2 nd revised ed.; Hall, D. G., Ed.; Wiley‐VCH:
Weinheim, 2011.
(9) For examples of the preparation and functionalization of chiral
4‐borylpiperidines, see: (a) Lessard, S.; Peng, F.; Hall, D. G. J. Am. Chem. Soc.
2009, 131, 9612. (b) Ding, J.; Hall, D. G. Angew. Chem., Int. Ed. 2013, 52, 8069.
(c) Ding, J.; Rybak, T.; Hall, D. G. Nat. Commun. 2014, 5, 5474.
(10) Fowler, F. W. J. Org. Chem. 1972, 37, 1321.
(11) The author have reported the first copper(I)‐catalyzed regio‐ and
enantioselective protoborylation of carbocyclic 1,3‐dienes, see: Sasaki, Y.;
Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226
(12) The triarylphosphine type ligand showed high reactivity toward
4‐aryl‐1,2‐dihydropyridines because an aryl group at 4‐position could lower
the LUMO levels of 1,2‐dihydropyridines by extension of the conjugated
system in the substrate, which could promote the insertion reaction of a
borylcopper(I) intermediate.
(13) The author also conducted the enantioselective borylation of
4‐methyl‐1,2‐dihydropyridine 2p, but the reaction provided the primary
boronate 4p as shown in below scheme. The detail is now under
investigation.
(14) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nat.
Chem. 2014, 6, 584.
(15) Recent enantioselective syntheses of ( ) ‐paroxetine, see: (a) Hynes, P. S.;
Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389. (b) Kim, M.‐H.; Park, Y.;
Jeong, B.‐S.; Park, H.‐G.; Jew, S.‐S. Org. Lett. 2010, 12, 2826. (c) Krautwald, S.;
Schafroth, M. A.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020.
(d) White, N. A.; Ozboya, K. E.; Flanigan, D. M.; Rovis, T. Asian J. Org. Chem.
2014, 3, 442.
(16) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(17) Fenger, I.; Drian, C. L. Tetrahedron Lett. 1998, 39, 4287.
CuCl (5 mol %)(R,R)-QuinoxP* (5 mol %)B2(pin)2 (1.2 equiv)
K(O-t-Bu) (20 mol %)MeOD (2 equiv)THF, 0C, 12 h
NO
MeO2p 4p
44%, 71% ee
Me
NO
MeO
B(pin)
281
(18) The calculated structures have been included in SI.
(19) Abou Jneid, R.; Ghoulami, S.; Martin, M.; Dau, E. T. H.; Travert, N.;
Al Mourabit, A. Org. Lett. 2004, 6, 3933.
(20) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. N. J. Org. Chem. 1989, 54,
5930.
(21) Sadhu, K.; Matteson, D. S. Organometallics 1985, 4, 1687.
Monterde, M. I.; Nazabadioko, S.; Rebolledo, F.; Brieva, R.; Gotor, V.
Tetrahedron Asymmetry 1999, 10, 3449.
(22) Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G.
E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, Jr., J. A. Montgomery, J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C.
Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
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Gaussian, Inc., Wallingford CT, 2009.
282
Summary of this thesis
Organoboron compounds have found wide application ranging from
organic synthesis to anti‐cancer medicine and organic materials. Thus, the
development of simple, mild and efficient synthetic method for their
preparation is in great demand. With this in mind, the author has
investigated the copper(I)‐catalyzed novel borylation reactions.
In chapters 1 and 2, the auther has developed the new method for the
synthesis of various alkylboronate esters from alkyl halides through
copper(I) catalysis. The boryl substitution of alkyl halides described in
chapter 1 provides a direct umpolung pathway for the conventional carbon
nucleophile method, and has high functional group compatibility and
interesting stereochemical‐controlling properties. The author believes that
this procedure will be a powerful synthetic method for a broad range of
alkylboronates, including those that could not be synthesized by previous
methods. The borylative cyclization reaction described in chapter 2 offers an
efficient route to various small carbocyclic boronates from readily available
starting materials.
In chapters 3, the auther has developed the enantioselective borylation
reaction of alkenylsilanes catalyzed by a copper(I)/chiral diphosphine
complex. The product can be converted into various functionalized chiral
compounds such as aminoalcohols by stepwise functionalization of a boryl
and a silyl groups.
In chapters 4 and 5, the auther has developed the enantioselective
borylation reaction of aldehydes catalyzed by a copper(I)/chiral diphosphine
complex and conducted the theoretical study for deep understanding of the
reaction mechanism. The newly synthesized chiral α‐alkoxyorganoboronate
esters described in chapter 4 could be transformed to functionalized chiral
alcohol derivatives using stereospecific C–C bond forming reactions.
In chapters 6, the auther has developed the enantioselective dearomative
borylation reaction of aromatic compound, indoles catalyzed by a
copper(I)/chiral diphosphine complex. This is the first example for the C–B
bond forming dearomatization of aromatic compounds to give the
synthetically useful chiral N‐heterocyclic boronate directly.
In chapters 7, the auther has developed the enantioselective borylation
reaction of 1,2‐dihydropyridines catalyzed by a copper(I)/chiral diphosphine
283
complex. This new method provides simple, mild and rapid access to a
variety of chiral piperidines in combination with the stereospecific
transformation of a stereogenic C–B bond.
These studies in this thesis will be particularly valuable toward the
development and design of novel borylation reactions with transition‐metal
catalysis.
284
List of Publications
Chapter 1
Copper(I)‐Catalyzed Boryl Substitution of Unactivated Alkyl Halides
Ito, H.; Kubota, K.
Org. Lett. 2012, 14, 890.
Chapter 2
Copper(I)‐Catalyzed Borylative exo‐Cyclization of Alkenyl Halides
Containing Unactivated Double‐Bond
Kubota, K.; Yamamoto, E.; Ito, H.
J. Am. Chem. Soc. 2013, 135, 2635.
Chapter 3
Regio‐ and Enantioselective Monoborylation of Alkenylsilnes Catalyzed by
an Electron‐Donating Chiral‐Phosphine Copper(I) Complex
Kubota, K.; Yamamoto, E.; Ito, H.
Adv. Synth. Catal. 2013, 355, 3527.
Highlighted in Synfacts 2014.
Chapter 4
Copper(I)‐Catalyzed Enantioselective Nucleophilic Borylation of Aldehydes
Kubota, K.; Yamamoto, E.; Ito, H.
J. Am. Chem. Soc. 2015, 137, 420.
Chapter 5
Computational Insight into the Enantioselective Borylation of Aldehydes
Catalyzed by Chiral Bisphosphine Copper(I) Complexes
Kubota, K.; Mingoo, J.; Ito, H.
To be submitted.
285
Chapter 6
Copper(I)‐Catalyzed Enantioselective Borylative Dearomatization of Indoles
Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H.
Angew. Chem., Int. Ed. 2015, 54, 8809.
Chapter 7
Copper(I)‐Catalyzed Regio‐ and Enantioselective Borylation of
1,2‐Dihydropyridines
Kubota, K.; Watanabe, Y.; Hayama, K.; Ito, H.
To be submitted.
Other Publications
1.
Silicon‐Tethered Strategy for Copper(I)‐Catalyzed Stereo‐ and Regioselective
Alkylboration of Alkynes
Kubota, K.; Iwamoto, H.; Yamamoto, E; Ito, H. Org. Lett. 2015, 17, 620.
2.
Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic
Enantioselective Desymmetrization of 1,1‐Diborylalkanes via Suzuki–
Miyaura Cross‐Coupling
Sun, H.; Kubota, K.; Hall, D. G. Chem. Eur. J. 2015, Early View.
3.
Copper(I)‐Catalyzed Carbon–Halogen Bond‐Selective Boryl Substitution of
Alkyl Halides Bearing Terminal Alkene Moieties
Iwamoto, H.; Kubota, K.; Yamamoto, E; Ito, H.
Chem. Commum. 2015, 51, 9655.
4.
Copper(I)‐Catalyzed Diastereoselective Borylative Exo‐Cyclization of
Alkenyl Aryl Ketones
Yamamoto, E.; Kojima, R.; Kubota, K.; Ito, H.
Synlett 2015, Just Accepted.
286
5. (review)
Selective Synthesis of Organoboron Compounds with Copper(I)‐Phosphine
Complex Catalysts
Yamamoto, E.; Takenouchi, Y.; Kubota, K.; Ito, H.
J. Synth. Org. Chem. Jpn. 2014, 72, 758.
6. (review)
Topochemical Photocyclizations for the Synthesis of Two‐Dimensional
Polymers
Kubota, K. J. Synth. Org. Chem. Jpn. 2014, 72, 834.
287
Acknowledgements
The studies presented in this thesis have been carried out under the
direction of Professor Hajime Ito at the Division of Chemical Process
Engineering, Graduate School of Engineering, Hokkaido University during
20112016. The studies are concerned with the development of catalytic
borylation reactions using borylcopper(I) intermediates.
The auther would like to express his deepest gratitude to Professor Hajime
Ito whose kind guidance, enormous supports and insightful comments were
invaluable during the course of his study. The author particularly indebted to
Associate Professor Tatsuo Ishiyama for his helpful advice and stimulating
discussions during the cource of his study. The author also would like to
thank Assistant Professor Tomohiro Seki for their helpful discussions and
kind supports. The author also would like to thank Professor Tetsuya
Taketugu, Associate Professor Satoshi Maeda and Dr. Ryohei Uemastu for
their valuable disccusions about theoretical studies.
The author is grateful to thank Dr. Eiji Yamamoto, Dr. Ikuo Sasaki, Mr.
Yuta Tkenouchi, Mr. Ryoto Kojima, Mr. Hiroaki Iwamoto, Mr. Jin Mingoo, Mr.
Keiichi Hayama, Mr. Yuta Watanabe and Mr. Shun Osaki and other members
of Professor Ito’s research group for their good collaboration and for
providing a good working atmosphere.
This work supported by Reserch Fellowships of the Japan Society for the
Promotion of Science for Young Scientists.
Koji Kubota
Graduate School of Chemical Science and Engineering
Hokkaido Univerity
2016